CN115785084B

CN115785084B - Pyrimidine derivatives and their use in medicine

Info

Publication number: CN115785084B
Application number: CN202211031354.3A
Authority: CN
Inventors: 习宁; 李晓波; 李敏雄; 席云龙; 冯学金; 夏娟
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2022-08-26
Filing date: 2022-08-26
Publication date: 2024-01-16
Anticipated expiration: 2042-08-26
Also published as: CN115785084A

Abstract

The invention belongs to the field of medicines, and relates to aminopyrimidine derivatives and application thereof in medicines. In particular, the present invention relates to compounds of general formula (I) or stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and their use in the manufacture of a medicament, in particular for the treatment and/or prophylaxis of cancer or autoimmune diseases mediated by PI 3K.

Description

Pyrimidine derivatives and their use in medicine

Technical Field

The invention belongs to the field of medicines, and particularly relates to novel compounds serving as kinase activity inhibitors, a method for preparing the novel compounds, a pharmaceutical composition containing the novel compounds and application of the novel compounds and the pharmaceutical composition in treating various diseases. More specifically, the compounds of the present invention are useful as inhibitors of phosphoinositide 3-kinases (PI 3Ks, such as pi3kα, pi3kβ, pi3kδ and pi3kγ) activity.

Background

Phosphoinositide 3-kinases (PI 3 kinases or PI3 Ks), which are a family of lipid kinases, play an important regulatory role in many cellular processes, such as survival, proliferation and differentiation of cells. As a major contributor in downstream transduction of Receptor Tyrosine Kinases (RTKs) and G protein-coupled receptors (GPCRs), PI3Ks activate the serine-threonine protein kinase AKT (also known as Protein Kinase B (PKB)) and other downstream pathways by generating phospholipids, signaling from various growth factors and factors into cells. The oncogene or PTEN (homologous phosphatase-tensin) is the most important inverse regulator in the PI3K signaling pathway ("Small-molecule inhibitors of the PI K signaling network." Future Med chem.2011,3 (5), 549-565).

The PI3K family is divided into three classes (I, II and III) based on structure, regulation and substrate specificity (Vanhaesebroeck, b. Et al The emerging mechanisms of isoform-specific PI3K signaling. Nat Rev Mol Cell Biol,2010.11 (5): pages 329-41). Class I PI3 ks are further classified into class IA and class IB based on sequence similarity. Class IA PI3K contains three closely related kinases, PI3K alpha, PI3K beta and PI3K delta, which exist as heterodimers consisting of a catalytic subunit (p110alpha, p110beta or p110delta) and a regulatory subunit (p 85) (Yu, J. Et al., regulation of the p/p 110 phosphotidylinosol 3' -kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p, 110, 85 regulatory ultrasound Cell Biol,1998.18 (3): pages 1379-87; carpenter, C.L. et al., phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 don of the 85-kDa ultrasound J Biol Chem,1993.268 (13): alpha 9478-83; zhang, X. Et al., structure of lipid kinase p, 110beta/p85, beta elucidates an unusual SH-mediated inhibitory membrane mol, 2011.41 (5-87) Bunge, 677-78, 7-37, 37-37). Class IB PI3 Ks include only PI3Kγ, which consists of p110γ (Stoyanov, B.et al, cloning and characterization of a G protein-activated human phosphoinositide-3kinase science,1995.269 (5224): 690-3. Page.) catalytic subunits associable with p101 (Stephens, L.R. et al, the G beta gamma sensitivity of a P13K is dependent upon a tightly associated adaptor, p101.Cell,1997.89 (1): pages 105-14), roles of G beta gamma in membrane recruitment and activation of p gamma/p101 phosphoinositide 3-kinase gamma.J Cell Biol,2003.160 (1): pages 89-99), or p84 (Suire, S. et al, p84, a new Gbetagamma-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110gamma.Curr Biol,2005.15 (6): pages 566-70).

PI3kα and PI3kδ react with signaling (Inukai, K. Et al, five isoforms of the phosphatidylinositol-kinase regulatory subunit exhibit different associations with receptor tyrosine kinases and their tyrosine phosphinylations.febs Lett,2001.490 (1-2): pages 32-8) that is typically carried out by the Receptor Tyrosine Kinase (RTK), while PI3kγ signals (Stoyanov, b. Et al, cloning and characterization of a Gprotein-activated human phosphoinositide-3kinase. Science,1995.269 (5224): pages 690-3; mailer, u., a. Babich and b. Nurnberg, roles of non-catalytic subunits in gbetagamma-induced activation of class I phosphoinositide-kinase isoforms beta and gamma.j Biol Chem,1999.274 (41): pages 29311-7), and PI3kβ signals (Kurosu, h. Et al, heterodimeric phosphoinositide-kinase consisting of p and 110 pept.j.biol (beta is synergistically activated by the betagamma subunits of G proteins and phosphotyrosyl) Chem (39) pages 24252). The expression of the pi3kα and pi3kβ isoforms is ubiquitous, whereas the expression pattern of pi3kδ and pi3kγ seems to be more restricted, both of which are mainly found in leukocytes (Kok, K., b.geering and b.vanhaesebroeck, regulation of phosphoinositide-kinase expression in health and diseases. Trends Biochem Sci,2009.34 (3): pages 115-27).

In contrast to pi3kα, there are no somatic mutations identified in the pi3kβ isoform. However, overexpression of PI3K beta has been considered necessary for transformation induced by deletion or inactivation of PTEN tumor suppressors in vitro and in vivo (Torbett NE, luna A, knight ZA et al, A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI K iso-selective inhibition.biochem J2008;415:97-110;Zhao JJ,Liu Z,Wang L,Shin E,Loda MF,Roberts TM,The oncogenic properties of mutant p110a and p110b phosphatidylinositol 3-kinases in human mammary epithelial cells.Proc Natl Acad Sci USA 2005; 102:1843-8). Recently, the use of shRNA demonstrated that downregulation of p110β, but not p110α, resulted in inactivation of the PI3K pathway and subsequently in tumor cell growth in PTEN-deficient cancer cells in vitro and in vivo (Wee S, wiederschain, maira S-M, loo a, miller C et al, PTEN-deficient cancers depend on PI3kcb.proc Natl Acad Sci2008; 105:13057-13062). Because of its role in PTEN-free tumors, PI3K beta has been reported to be also critical for the transformation phenotype in PTEN-free prostate cancer models (Jia S, liu Z, zhang S, liu P, zhang L et al, essential roles of PI K-P110b in cell growth, metanolism and turbogesis. Nature 2008; 10:1038).

In summary, PI3K beta is a promising target for Cancer and other syndromes associated with PTEN deficiency (Hollander, M.christine; blumethoal, gideon M, dennis, phillip, PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nature reviews/Cancer 2011; 11:289-301). Thus, there is a strong need for novel PI3K beta inhibitors to treat cancer, particularly PTEN deficient cancers.

A series of PI3K beta selective inhibitor patent applications, including WO2018057810, WO2018178280, etc., have been disclosed, and research and use of PI3K beta selective inhibitors has progressed to some extent, but there is still a great room for improvement, and there is still a need to continue to research and develop new PI3K beta selective inhibitors.

Disclosure of Invention

The present invention provides a compound, or a pharmaceutical composition thereof, that is useful as a PI3K kinase inhibitor. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or disorders by inhibition of PI3K kinase activity by said compounds. The invention further describes a preparation method of the compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.

Specifically:

in one aspect, the invention relates to a compound which is a compound of the structure shown in formula (I) or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound shown in formula (I):

wherein:

R ¹ and R is ² Each independently is H, D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl or C _1-6 Alkoxy, wherein said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _1-6 Alkoxy groups are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, halogen, -NO ₂ -CN, oxo, C _1-6 Alkyl and C _1-6 Substituted by a substituent of haloalkyl;

a is a heteroaryl group of 5 to 12 atoms, wherein the heteroaryl group of 5 to 12 atoms is independently optionally substituted with 1, 2, 3, 4 or 5R ³ Substituted;

R ³ is D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group;

b is C _3-8 Cycloalkyl or heterocyclic groups of 3-8 atoms, wherein said C _3-8 Cycloalkyl and 3-8 atom heterocyclyl are each independently optionally substituted with 1, 2, 3, 4 or 5R ⁴ Substituted with a group;

R ⁴ is D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, -OR ^a 、-C(＝O)R ^a 、-C(＝O)OR ^a 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b 、C _3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C _6-10 Aryl or heteroaryl of 5-12 atoms, wherein said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, C _3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C _6-10 Aryl and heteroaryl consisting of 5 to 12 atoms are each independently optionally substituted with 1,2,3, 4 or 5 groups selected from D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, C _1-6 Haloalkoxy and C _1-6 Substituted by a substituent of hydroxyalkoxy;

each R is ^a And R is ^b H, D, C independently _1-6 Alkyl, C _3-8 Cycloalkyl or heterocyclic groups of 3-8 atoms, wherein said C _1-6 Alkyl, C _3-8 Cycloalkyl and 3-8 atom heterocyclyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, halogen, oxo, -NO ₂ 、-CN、-OH、-NH ₂ -COOMe and-COOH;

w is N or CH;

R ⁵ h, D and halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl or C _1-6 A haloalkyl group;

R ⁶ ground is H, D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group;

m is 0,1,2,3 or 4;

wherein the compound does not include the following:

in some embodiments, the compounds of the present invention have a structure represented by formula (II):

Therein, A, B, R ¹ 、R ² 、R ⁵ 、R ⁶ Each of W and m has the meaning described in the present invention.

In some embodiments, A is a heteroaryl of 5 to 10 atoms, wherein the heteroaryl of 5 to 10 atoms is independently optionally substituted with 1, 2, 3, 4, or 5R ³ Substituted;

b is C _3-6 Cycloalkyl or heterocyclic groups of 3-6 atoms, wherein said C _3-6 Cycloalkyl and 3-6 atom heterocyclyl are each independently optionally substituted with 1, 2, 3, 4 or 5R ⁴ The groups are substituted.

In other embodiments, A is Wherein said A is independently optionally substituted with 1, 2, 3, 4 or 5R ³ Substituted with a group; wherein R is ³ Having the meaning as described in the present invention;

b is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted with 1, 2, 3, 4 or 5R ⁴ Substituted with a group; wherein R is ⁴ Having the meaning described in the present invention.

In some embodiments, R ¹ And R is ² Each independently is H, D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl or C _1-4 Alkoxy, wherein said C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl and C _1-4 Alkoxy groups are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, halogen, -NO ₂ -CN, oxo, C _1-4 Alkyl and C _1-4 Substituted by a substituent of haloalkyl;

R ³ is D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy or C _1-4 An alkylamino group;

R ⁴ d, F, cl, br and-NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Alkylamino, -OR ^a 、-C(＝O)R ^a 、-C(＝O)OR ^a 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b 、C _3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C _6-10 Aryl or heteroaryl of 5 to 10 atoms, wherein the radicals areC of (2) _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Alkylamino, C _3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C _6-10 Aryl and heteroaryl consisting of 5 to 10 atoms are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Alkylamino, C _1-4 Haloalkoxy and C _1-4 Substituted by a substituent of hydroxyalkoxy;

each R is ^a And R is ^b H, D, C independently _1-4 Alkyl, C _3-6 Cycloalkyl or heterocyclic groups of 3-6 atoms, wherein said C _1-4 Alkyl, C _3-6 Cycloalkyl and 3-6 atom heterocyclyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from D, halogen, oxo, -NO ₂ 、-CN、-OH、-NH ₂ -COOMe and-COOH;

R ⁵ h, D and halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl or C _1-4 A haloalkyl group;

R ⁶ h, D and halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy or C _1-4 An alkylamino group.

In other embodiments, R ¹ And R is ² Each independently is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, methoxy, ethoxy, 1-propoxy or 2-propoxy, wherein said methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, methoxy, ethoxy, 1-propoxy and 2-propoxy are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br,I、-NO ₂ -CN, oxo, methyl, ethyl, n-propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ and-CH ₂ CF ₃ Is substituted by a substituent of (2);

R ³ d, F, cl, br, I and-NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, 1-propoxy, 2-propoxy, N-methylamino, N-ethylamino, N-dimethylamino or N, N-diethylamino;

R ⁴ d, F, cl, br, I and-NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, 1-propoxy, 2-propoxy, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, -OR ^a 、-C(＝O)R ^a 、-C(＝O)OR ^a 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b A cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furanyl, triazolyl, phenyl, pyridinyl or pyrimidinyl group, wherein said methyl, ethyl, N-propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furanyl, triazolyl, phenyl, pyridinyl and pyrimidinyl group are each independently optionally substituted with 1, 2, 3, 4 or 5 amino groups selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, iso-propylPropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, isopropoxy, N-methylamino, N-diethylamino, -OCF ₃ 、-OCH ₂ CF ₃ 、-OCH ₂ OH and-OCH ₂ CH ₂ A substituent of OH;

each R is ^a And R is ^b Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from D, F, cl, br, I, oxo, -NO ₂ 、-CN、-OH、-NH ₂ -COOMe and-COOH;

R ⁵ h, D, F, cl, br, I and-NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ or-CH ₂ CF ₃ ；

R ⁶ H, D, F, cl, br, I and-NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, 1-propoxy, 2-propoxy, N-methylamino, N-ethylamino, N-dimethylamino or N, N-diethylamino.

In one aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the pharmaceutical compositions of the present invention further comprise one or more pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or combinations thereof.

In some embodiments, the pharmaceutical compositions provided herein may further comprise one or more therapeutic agents.

In other embodiments, the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.

In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing, treating or alleviating a disease associated with aberrant expression of PI3K kinase.

In some embodiments, the PI3 ks of the invention are pi3kβ kinases.

In other embodiments, the disease associated with aberrant expression of PI3K kinase described herein is an inflammatory disease, an autoimmune disease, or a cancer.

In some embodiments, the cancer of the invention is a cancer in which the homologous phosphatase-tensin gene is deleted.

In still other embodiments, the disease associated with aberrant expression of PI3K kinase described herein is acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, T-cell lymphoma, B-cell lymphoma, myelodysplastic syndrome, myeloproliferative disease, fahrenheit macroglobulinemia, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, myasthenia gravis, rheumatoid arthritis, multiple sclerosis, autoimmune hemolytic anemia, vasculitis, lupus nephritis, pemphigus, membranous nephropathy, asthma, psoriasis, chronic obstructive pulmonary disease, or lupus.

In another aspect, the present invention relates to methods for the preparation, isolation and purification of the compounds of formula (I) or formula (II).

The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.

"stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.

"chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.

"diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, racemates and Resolutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2) ^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valance tautomers) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and other instances where it does not. For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds.

The term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. The term "optionally substituted with … …" may be used interchangeably with the term "unsubstituted or substituted with …," i.e., the structure is unsubstituted or substituted with one or more substituents described herein; when the number of the substituents is greater than 1, the substituents may be the same or different from each other. For example, "optionally substituted with 1, 2, 3, 4, or 5 groups selected from … …" as described herein, the substituents may be the same or different when the number of substituents is greater than 1.

In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C _1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl and C ₆ An alkyl group.

In the present invention, "C _n1-n2 "means that the group contains a natural number of carbon atoms of n1-n2, n1 and n2 are both non-0, and n2 is greater than n1, and" n1-n2 "includes n1, n2 and any natural number therebetween. Such as C _1-6 Alkyl represents an alkyl group having 1 to 6 carbon atoms; c (C) ₁ - ₆ Alkoxy represents an alkoxy group having 1 to 6 carbon atoms; c (C) _3-6 Carbocyclyl represents carbocyclyl having 3 to 6 carbon atoms.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein means a saturated, straight or branched, monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other casesIn embodiments, the alkyl group contains 1 to 6 carbon atoms, denoted C _1-6 An alkyl group; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms, represented by C _1-4 An alkyl group; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms, denoted C _1-3 An alkyl group.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) ₃ ) Ethyl (Et, -CH) ₂ CH ₃ ) N-propyl (n-Pr, -CH) ₂ CH ₂ CH ₃ ) Isopropyl (i-Pr, -CH (CH) ₃ ) ₂ ) N-butyl (n-Bu, -CH) ₂ CH ₂ CH ₂ CH ₃ ) Isobutyl (i-Bu, -CH) ₂ CH(CH ₃ ) ₂ ) Sec-butyl (s-Bu, -CH (CH) ₃ )CH ₂ CH ₃ ) Tert-butyl (t-Bu, -C (CH) ₃ ) ₃ ) N-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyl (-CH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butyl (-C (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butyl (-CH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-1-butyl (-CH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-1-butyl (-CH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) N-hexyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-hexyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ) 3-hexyl (-CH (CH) ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) 2-methyl-2-pentyl (-C (CH) ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl (-CH (CH) ₃ )CH(CH ₃ )CH ₂ CH ₃ ) 4-methyl-2-pentyl (-CH (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ ) 3-methyl-3-pentyl (-C (CH) ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl (-CH (CH) ₂ CH ₃ )CH(CH ₃ ) ₂ ) 2, 3-dimethyl-2-butyl (-C (CH) ₃ ) ₂ CH(CH ₃ ) ₂ ) 3, 3-dimethyl-2-butyl (-CH (CH) ₃ )C(CH ₃ ) ₃ ) N-heptyl, n-octyl, and the like.

The term "alkenyl" denotes a straight-chain or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, in which there is at least one site of unsaturation, i.e. one carbon-carbon sp ² A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms, denoted C _2-6 Alkenyl groups; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms, represented as C _2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-ch=ch) ₂ ) Allyl (-CH) ₂ CH＝CH ₂ ) 1-propenyl (propenyl, -ch=ch-CH) ₃ ) Etc.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2 to 8 carbon atoms; in other embodiments, alkynyl groups contain 2 to 6 carbon atoms and are represented as C _2-6 Alkynyl; in still other embodiments, alkynyl groups contain 2 to 4 carbon atoms, denoted C _2-4 Alkenyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH) ₂ C.ident.CH), 1-propynyl (propynyl, -C.ident.C-CH ₃ ) Etc.

The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms, represented byC _1-6 An alkoxy group; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms, represented by C _1-4 An alkoxy group; in still other embodiments, the alkoxy group contains 1 to 3 carbon atoms, represented by C _1-3 An alkoxy group. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) ₃ ) Ethoxy (EtO, -OCH) ₂ CH ₃ ) 1-propoxy (n-PrO, n-propoxy, -OCH) ₂ CH ₂ CH ₃ ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) ₃ ) ₂ ) 1-butoxy (n-BuO, n-butoxy, -OCH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) ₂ CH(CH ₃ ) ₂ ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) ₃ )CH ₂ CH ₃ ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) ₃ ) ₃ ) 1-pentoxy (n-pentoxy, -OCH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentoxy (-OCH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentoxy (-OCH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butoxy (-OC (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butoxy (-OCH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-l-butoxy (-OCH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-l-butoxy (-OCH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) And so on.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl and alkoxy groups are defined specifically as described herein. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

The term "hydroxyalkoxy" means that the alkoxy group is substituted with one or more hydroxy groups, examples of which include, but are not limited toLimited to, -OCH ₂ OH、-OCH ₂ CH ₂ OH, and the like.

The term "cycloalkyl" means a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring carbon atoms. In some embodiments, cycloalkyl groups comprise 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups comprise 3 to 8 carbon atoms; in still other embodiments, cycloalkyl groups contain 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The terms "heterocycle", "heterocyclyl" or "heterocyclic" are used interchangeably herein to refer to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 ring atoms in which one or more atoms in the ring are independently replaced by heteroatoms having the meaning as described herein, and the ring may be fully saturated or contain one or more unsaturations, but none of the aromatic rings. In some embodiments, the "heterocycle", "heterocyclyl" or "heterocyclic" group is a monocyclic ring of 3 to 8 atoms (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S where S or P is optionally substituted with one or more oxygen atoms to give a compound like SO, SO ₂ A group of PO), or 7-12 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a ring like SO, SO ₂ Groups of PO). In other embodiments, the "heterocycle", "heterocyclyl" or "heterocyclic" group is a monocyclic ring of 3 to 6 atoms (2 to 4 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S where S or P is optionally substituted with one or more oxygen atoms to give a compound such as SO, SO ₂ Groups of PO). The heterocyclyl group is optionally substituted with one or more substituents described herein.

The heterocyclic group may be a carbon group or a heteroatom group; wherein, is a ring-CH ₂ The group may optionally be replaced by-C (=o) -and the sulphur atom of the ring may optionally be oxidisedIn the form of an S-oxide, the nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxalkyl, homopiperazinyl, homopiperidinyl, oxacycloheptyl, thietanyl, oxaazaRadical, diaza->Radical, thiazal->Radical, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic groups-CH ₂ Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl, pyrimidinedionyl, and the like. Examples of sulfur atoms in the heterocyclyl group that are oxidized include, but are not limited to, sulfolane, thiomorpholino 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.

The term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains a ring of 3 to 7 atoms, and wherein one or more attachment points are attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.

The term "heteroaryl" or "heteroaromatic ring" means a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing 5 to 14 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. Heteroaryl groups are typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, a heteroaryl group consisting of 5 to 10 ring atoms comprises 1, 2, 3, or 4 heteroatoms independently selected from O, S and N; in other embodiments, the heteroaryl group consisting of 5 to 6 ring atoms is a monocyclic ring system and comprises 1, 2, 3, or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1, 3-dithiotriazinyl, 1, 3-dithio, 3-triazolyl, 1, 3-triazolyl; the following bicyclic rings are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), azaquinolinyl, imidazo [1,2-a ] pyridinyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, and the like.

The terms "j-k ring atoms" or "j-k members" are used interchangeably herein to mean that the cyclic group is composed of j-k ring atoms, including carbon atoms and/or O, N, S, P and like heteroatoms. Each of j and k is independently any non-zero natural number, and k > j; the term "j-k" includes j, k and any natural number therebetween. For example, "3-8 atom or 3-8 membered", "3-6 atom or 3-6 membered", "5-10 atom or 5-10 membered" or "5-6 atom or 5-6 membered" means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10) or 5-6 (i.e., 5 or 6) ring atoms including heteroatoms such as carbon atoms and/or O, N, S, P. Specifically, for example, "heteroaryl consisting of 5 to 10 ring atoms" or "5 to 10 membered heteroaryl" represents heteroaryl comprising 5, 6, 7, 8, 9 or 10 ring atoms, wherein 5, 6, 7, 8, 9 or 10 is represented as the number of ring atoms, such as pyridyl is heteroaryl consisting of 6 ring atoms or 6 membered heteroaryl.

The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state forms of P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom of the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R is a substituent according to the invention).

The term "halogen" or "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups.Some of these are, for example, alkylamino groups of one or two C _1-6 An alkyl group is attached to a nitrogen atom. Other embodiments are those wherein the alkylamino group is substituted with one or two C _1-3 An alkyl substituted amino group. Suitable alkylamino groups may be mono-or dialkylamino, such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N, N-dimethylamino (dimethylamino), N, N-diethylamino (diethylamino), and the like.

As described herein, substituents (R ⁵ ) _m The ring system formed by a ring linked to the centre by a bond representing m substituents R ⁵ The substitution may be at any substitutable position or at any reasonable position on the ring in which it is located. For example, formula d represents that the G ring may be surrounded by m R ⁵ Substitution, when m is greater than 1, each R ⁵ May be independently selected from the same or different substituent groups.

The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, by "protecting group for an amino group" is meant a substituent attached to the amino group to block or protect the functionality of the amino group in the compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include acetyl and silyl. "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typically the carboxyl protecting group includes-CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. For a pair of General description of protecting groups can be found in the literature: t W.Greene, protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not generally produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, etc., when administered to humans. Preferably, the term "pharmaceutically acceptable" as used herein refers to use in animals, particularly in humans, approved by the federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia.

The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water and aqueous solutions saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly injectable solutions. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences" of e.w. martin.

The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C _1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound contains a hydroxyl group, i.e., it can be acylated to give the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: T.Higuchi and V.stella, pro-drugs as Novel Delivery Systems, vol.14of the A.C.S. symposium Series, edward B.Roche, ed., bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

"metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: S.M. Berge et al describe pharmaceutically acceptable salts in detail in J.pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, and the like, or by other methods described in the literature such as ion exchange. Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts, such as ammonium salts and metal salts of groups I to XII of the periodic table, and organic base salts, such as salts with primary, secondary and tertiary amines.

"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.

The term "treating" as used herein refers in some embodiments to ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.

The term "therapeutically effective amount" means that the amount of the compound, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of further suitable salts can be found in Properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include solvated and unsolvated forms.

Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H， ³ H， ¹¹ C， ¹³ C， ¹⁴ C， ¹⁵ N， ¹⁷ O， ¹⁸ O， ¹⁸ F， ³² P， ³⁵ S， ³⁶ Cl and Cl ¹²⁵ I. Isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation herein as using a suitable isotopically-labeled reagent in place of the originally used unlabeled reagent.

All tautomeric forms of the compounds of the invention are included within the scope of the invention unless otherwise indicated. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

The term "cancer" as used herein refers to or describes a physiological condition in a patient that is generally characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or malignant lymphoproliferative disease (lymphoid malignancies). More specific examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer (NSCLC)), esophageal cancer, peritoneal cancer, gastric cancer (gastric or stomach cancer) (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer (liver cancer), bladder cancer, breast cancer, colon cancer, rectal cancer, appendiceal cancer, small intestine cancer, endometrial or uterine cancer, salivary gland cancer, renal or renal cancer (kidney or renal cancer), prostate cancer, vulval cancer, thyroid cancer, anal cancer, penile cancer, and head and neck cancer.

Detailed description of the Compounds of the invention

The present invention provides a compound or a pharmaceutical composition thereof, which is useful as an inhibitor of PI3K kinase, in particular PI3K beta kinase. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or disorders by inhibiting the activity of PI3K beta kinase with said compounds. The invention further describes a method for synthesizing the compounds. The compounds of the invention exhibit improved biological activity and pharmacokinetic properties.

In one aspect, the present invention relates to a compound which is a compound of formula (I), or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),

In some embodiments, R ¹ And R is ² Each independently is H, D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl or C _1-6 Alkoxy, wherein said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _1-6 Alkoxy groups are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, halogen, -NO ₂ -CN, oxo, C _1-6 Alkyl and C _1-6 The substituent of the haloalkyl group is substituted.

In some embodiments, R ¹ And R is ² Each independently is H, D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl or C _1-4 Alkoxy, wherein said C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl and C _1-4 Alkoxy groups are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, halogen, -NO ₂ -CN, oxo, C _1-4 Alkyl and C _1-4 The substituent of the haloalkyl group is substituted.

In other embodiments, R ¹ And R is ² Each independently is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, methoxy, ethoxy, 1-propoxy or 2-propoxy, wherein said methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, methoxy, ethoxy, 1-propoxy and 2-propoxy are each independently and optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, -NO ₂ -CN, oxo, methyl, ethyl, n-propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ and-CH ₂ CF ₃ Is substituted by a substituent of (2).

In some embodiments, A is a heteroaryl group of 5 to 12 atoms, wherein the heteroaryl group of 5 to 12 atoms is independently optionallyGround cover 1, 2, 3, 4 or 5R ³ Substituted; wherein each R ³ Having the meaning described in the present invention.

In some embodiments, A is a heteroaryl of 5 to 10 atoms, wherein the heteroaryl of 5 to 10 atoms is independently optionally substituted with 1, 2, 3, 4, or 5R ³ Substituted; wherein each R ³ Having the meaning described in the present invention.

In still other embodiments, A is/> Wherein said A is independently optionally substituted with 1, 2, 3, 4 or 5R ³ Substituted with a group; wherein each R ³ Having the meaning described in the present invention.

In some embodiments, B is C _3-8 Cycloalkyl or heterocyclic groups of 3-8 atoms, wherein said C _3-8 Cycloalkyl and 3-8 atom heterocyclyl are each independently optionally substituted with 1, 2, 3, 4 or 5R ⁴ Substituted with a group; wherein each R ⁴ Having the meaning described in the present invention.

In some embodiments, B is C _3-6 Cycloalkyl or heterocyclic groups of 3-6 atoms, wherein said C _3-6 Cycloalkyl and 3-6 atom heterocyclyl are each independently optionally substituted with 1, 2, 3, 4 or 5R ⁴ Substituted with a group; wherein each R ⁴ Having the meaning described in the present invention.

In other embodiments, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are each independently optionally substituted with 1, 2, 3, 4, or 5R ⁴ Substituted with a group; wherein each R ⁴ Having the meaning described in the present invention.

In some embodiments, R ³ Is D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group.

In some embodiments, R ³ Is D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy or C _1-4 An alkylamino group.

In other embodiments, R ³ D, F, cl, br, I and-NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, 1-propoxy, 2-propoxy, N-methylamino, N-ethylamino, N-dimethylamino or N, N-diethylamino.

In some embodiments, R ⁴ Is D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, -OR ^a 、-C(＝O)R ^a 、-C(＝O)OR ^a 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b 、C _3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C _6-10 Aryl or heteroaryl of 5-12 atoms, wherein said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Alkylamino, C _3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C _6-10 Aryl and heteroaryl consisting of 5 to 12 atoms are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, C _1-6 Haloalkoxy groupsAnd C _1-6 Substituted by a substituent of hydroxyalkoxy; wherein each R ^a And R is ^b Having the meaning described in the present invention.

In some embodiments, R ⁴ D, F, cl, br and-NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Alkylamino, -OR ^a 、-C(＝O)R ^a 、-C(＝O)OR ^a 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b 、C _3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C _6-10 Aryl or heteroaryl of 5-10 atoms, wherein said C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _1-4 Alkylamino, C _3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C _6-10 Aryl and heteroaryl consisting of 5 to 10 atoms are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Alkylamino, C _1-4 Haloalkoxy and C _1-4 Substituted by a substituent of hydroxyalkoxy; each R is ^a And R is ^b Having the meaning described in the present invention.

In other embodiments, R ⁴ D, F, cl, br, I and-NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, 1-propoxy, 2-propoxy, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, -OR ^a 、-C(＝O)R ^a 、-C(＝O)OR ^a 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperonylOxazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furanyl, triazolyl, phenyl, pyridyl or pyrimidinyl, wherein the methyl, ethyl, N-propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furanyl, triazolyl, phenyl, pyridyl and pyrimidinyl are each independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, isopropoxy, N-methylamino, N-diethylamino, -OCF ₃ 、-OCH ₂ CF ₃ 、-OCH ₂ OH and-OCH ₂ CH ₂ A substituent of OH; wherein each R ^a And R is ^b Having the meaning described in the present invention.

In some embodiments, each R ^a And R is ^b H, D, C independently _1-6 Alkyl, C _3-8 Cycloalkyl or heterocyclic groups of 3-8 atoms, wherein said C _1-6 Alkyl, C _3-8 Cycloalkyl and 3-8 atom heterocyclyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from D, halogen, oxo, -NO ₂ 、-CN、-OH、-NH ₂ -COOMe and-COOH.

In some embodiments, each R ^a And R is ^b H, D, C independently _1-4 Alkyl, C _3-6 Cycloalkyl or heterocyclic groups of 3-6 atoms, wherein said C _1-4 Alkyl, C _3-6 Cycloalkyl and 3-6 atom heterocyclyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from D, halogen, oxo, -NO ₂ 、-CN、-OH、-NH ₂ Substituted by-COOMe and-COOHAnd (3) substitution.

In other embodiments, each R ^a And R is ^b Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from D, F, cl, br, I, oxo, -NO ₂ 、-CN、-OH、-NH ₂ -COOMe and-COOH.

In some embodiments, R ⁵ H, D and halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl or C _1-6 A haloalkyl group.

In some embodiments, R ⁵ H, D and halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl or C _1-4 A haloalkyl group.

In other embodiments, R ⁵ H, D, F, cl, br, I and-NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ or-CH ₂ CF ₃ 。

In some embodiments, R ⁶ H, D and halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 An alkylamino group.

In some embodiments, R ⁶ H, D and halogen, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy or C _1-4 An alkylamino group.

In other embodiments, R ⁶ H, D, F, cl, br, I and-NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, 1-propoxy, 2-propoxy, N-methylamino, N-ethylamino, N-dimethylamino or N, N-diethylamino.

In some embodiments, m is 0,1,2,3, or 4.

In some embodiments, W is N or CH.

In some embodiments, the compounds of the present invention do not include the following:

in another aspect, the present invention relates to compounds, or stereoisomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, of one of the following, but in no way limited to these compounds:

/>

in one aspect, the invention relates to pharmaceutical compositions comprising stereoisomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the aforementioned compounds.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.

In some embodiments, the PI3 ks of the invention are pi3kβ kinases.

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or formula (II).

Pharmaceutical compositions, formulations, administration and uses of the compounds of the invention

According to another aspect, the pharmaceutical composition of the present invention is characterized by comprising a compound of formula (I) or formula (II), a compound listed herein, or a compound of the examples, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical composition of the invention is effective to treat or ameliorate PI3K kinase mediated diseases in a patient.

The compounds of the invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly according to the needs of the patient, the compounds described in other aspects of the present invention, metabolites thereof, or residues thereof.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, including any solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, and the like, suitable for the particular target dosage form. As described in the following documents: in Remington, the Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York, in combination with the teachings of the literature herein, shows that different carriers can be used In the formulation of pharmaceutically acceptable compositions and their well-known methods of preparation. In addition to the extent to which any conventional carrier vehicle is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.

Materials that may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum proteins, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; a gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffer, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preserving and antioxidant agents.

Preferably, the compound is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier selected with regard to the form of administration and conventional pharmaceutical practice (referred to herein as a pharmaceutical carrier), which may be in the form of oral tablets, capsules, elixirs, syrups and the like.

For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral pharmaceutical component may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, and the like. Furthermore, suitable binders, lubricants, disintegrating agents, and coloring agents can also be added to the mixture, as desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, all dosage forms used being well known to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the mode of administration selected and standard pharmaceutical practice.

The compounds of the invention may be administered in intranasal form via topical use of suitable intranasal vehicles or by transdermal routes using transdermal patches. When administered in the form of a transdermal delivery system, the dosage administered is continuous rather than intermittent throughout the administration period.

The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

The compounds of the present invention are also coupled to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl amine methacrylate-phenol, polyhydroxyethyl asparaginol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

The dosage regimen of the compounds of the invention will vary with various factors known, such as the pharmacokinetic profile of the particular agent and its mode and route of administration; the race, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can make the decision and prescribe an effective amount of the drug to prevent, counter or arrest the progress of the cancer.

According to general guidelines, daily oral doses of each of the active ingredients used are in the range of from about 0.001 to 1000mg/kg body weight in order to achieve the indicated effect. For intravenous administration, the most preferred dosage range during conventional rate infusion is about 1 to about 10mg/kg body weight/minute. The compounds of the present invention may be administered once daily or may be administered in two, three or four times daily administrations.

Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1mg to about 1000mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally be about 0.5-95% of the total weight of the pharmaceutical composition.

When the compounds of the present invention are administered with other therapeutic agents, generally, the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage when administered alone, given the additional or synergistic effect of the therapeutic agents when administered in combination.

The compounds of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof are useful for preventing, treating or alleviating a disease associated with abnormal expression of PI3K kinase, particularly acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphoblastic leukemia, chronic myelogenous leukemia, multiple myeloma, T-cell lymphoma, B-cell lymphoma, myelodysplastic syndrome, myeloproliferative disease, megaloblastic, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, myasthenia gravis, rheumatoid arthritis, multiple sclerosis, autoimmune hemolytic anemia, vasculitis, lupus, nephritis, pemphigus, membranous nephropathy, asthma, psoriasis, chronic obstructive pulmonary disease or lupus.

General synthetic procedure

For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.

In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined herein, unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare other compounds of the present invention, and other methods for preparing compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.

The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company and used without further purification. Unless otherwise indicated, general reagents were purchased from Shandong chemical plant, guangdong chemical plant, guangzhou chemical plant, tianjin good, chemical company, tianjin Fuchen chemical plant, wuhan Xinhua remote technology development Co., qingdao Teng chemical Co., and Qingdao ocean chemical plant.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were dried over anhydrous sodium sulfate in advance for use.

The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant.

¹ H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. ¹ H NMR Spectroscopy with CDC1 ₃ 、DMSO-d ₆ 、CD ₃ OD or acetone-d ₆ TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet), q (quartet), m (multiplet), br (broadened, broad), br (broadened singlet, broad singlet), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constant J, expressed in hertz (Hz).

The measurement conditions for low resolution Mass Spectrometry (MS) data are: agilent 6120 four-stage HPLC-MS (column type: zorbax SB-C18, 2.1X130 mm,3.5 μm, 6min, flow rate 0.6mL/min. Mobile phase: 5% -95% (CH containing 0.1% formic acid) ₃ CN) in (H containing 0.1% formic acid) ₂ O) ratio, adoptedElectrospray ionization (ESI) was used and UV detection was performed at 210nm/254 nm.

The pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following abbreviations are used throughout the present invention:

the following schemes describe the steps for preparing the compounds of the present invention. Unless otherwise indicated, each A, B, R ² 、R ⁵ W and m have the definitions described in the present invention.

Reaction scheme 1

The [ (x) ray ]7) The compounds shown can be prepared by reaction scheme 1: the [ (x) ray ]1) The compound and the formula2) The compound is shown as the formula under the action of pyridine and triphenyl phosphite3) The compounds shown react to obtain the formula [ ]4) A compound shown in the specification; the [ (x) ray ]4) Removing protecting group from said compound under the action of strong acid to obtain the compound with formula [ ]5) A compound shown in the specification; the [ (x) ray ]5) The compound and the formula6) Nucleophilic substitution reaction of the compound to obtain the formula 7) The compounds shown.

Reaction scheme 2

The [ (x) ray ]14) The compounds shown can be prepared by reaction scheme 2: the [ (x) ray ]8) The compound shown reacts with thionyl chloride or oxalyl chloride to obtain the formula [ ]9) A compound shown; the [ (x) ray ]9) The compound shown in the formula3) The compounds are condensed to obtain the formula10) A compound shown; the [ (x) ray ]10) Shown isThe compound of the formula (II) is reacted with the formula (III) under the action of alkali11) The compounds shown react to obtain the formula [ ]12) A compound shown; the [ (x) ray ]12) Removing protecting group from said compound to obtain the formula%13) A compound shown; the [ (x) ray ]13) The compound shown in the formula6) The compounds shown react to obtain the formula14) The compounds shown.

Reaction scheme 3

The [ (x) ray ]14) The compounds shown can be prepared by reaction scheme 3: the [ (x) ray ]15) The esterification of the compounds shown gives the formula [ ]16) A compound shown; the [ (x) ray ]16) The compounds and the formula are17) The compounds are subjected to coupling reaction to obtain the formula18) A compound shown; the [ (x) ray ]18) The compounds shown are hydrolyzed to obtain the formula [ ]19) A compound shown; the [ (x) ray ]19) The compound is subject to ring closure reaction to obtain the formula20) A compound shown; the [ (x) ray ]20) The compounds and the formula are3) The compounds shown react to obtain the formula12) A compound shown; the [ (x) ray ] 12) The compound is subject to ring closure reaction to obtain the formula13) A compound shown; the [ (x) ray ]13) The compounds and the formula are6) The compounds shown react to obtain the formula14) The compounds shown.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further described below in conjunction with the examples.

Examples

Synthesis of fragment 1 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine

Reference is made to the synthesis of WO2015042077, example 3, steps 1-4.

Synthesis of fragment 2 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine

Reference is made to the synthesis of WO2015042077, example 2, steps 5-8.

Synthesis of fragment 3 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine

Reference is made to the synthesis of WO2015042078, example 12, steps 1-6.

Example 1 (S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3-hydroxycyclobutyl) quinazolin-4 (3H) -one

Synthesis of tert-butyl (S) - (1- (5-chloro-3- (3-hydroxycyclobutyl) -4-oxo-3, 4-dihydro-quinazolin-2-yl) ethyl) carbamate

To the reaction flask were added 2-amino-6-chlorobenzoic acid (0.69 g,4.0 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (0.76 g,4.0 mmol), pyridine (10 mL) and triphenyl phosphite (2.44 g,7.86 mmol). The reaction was reacted at room temperature for 14 hours, and then 3-aminocyclobutanol hydrochloride (0.49 g,4.0 mmol), DMF (2 mL) and KOH (0.44 g,7.9 mmol) were added to the system. After the addition, the reaction system was heated to 60℃for 10 hours. After the reaction was completed, it was cooled to room temperature, 3M hydrochloric acid (40 mL) was added thereto, and extracted with ethyl acetate (50 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =50/1) afforded the title compound as a colorless liquid (1.57 g, 99.7% yield).

MS(ESI,pos.ion)m/z:394.3[M+H] ⁺ .

Second step Synthesis of (S) -2- (1-aminoethyl) -5-chloro-3- (3-hydroxycyclobutyl) quinazolin-4 (3H) -one

To the reaction flask were added tert-butyl (S) - (1- (5-chloro-3- (3-hydroxycyclobutyl) -4-oxo-3, 4-dihydro-quinazolin-2-yl) ethyl) carbamate (1.0 g,2.5 mmol) and an ethyl acetate solution of hydrogen chloride (20 mL,3.0 mol/L). The reaction system was reacted at room temperature for 2 hours, and then concentrated under reduced pressure. To the residue was added saturated sodium carbonate solution to the system ph=7, stirred at room temperature for 0.5h, and extracted with ethyl acetate (50 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a colorless liquid (0.3 g, 40.0% yield).

MS(ESI,pos.ion)m/z:294.0[M+H] ⁺ .

Third step Synthesis of (S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3-hydroxycyclobutyl) quinazolin-4 (3H) -one

To the reaction flask was added successively (S) -2- (1-aminoethyl) -5-chloro-3- (3-hydroxycyclobutyl) quinazolin-4 (3H) -one (20 mg,0.07 mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (30 mg,0.14 mmol), DIPEA (30 mg,0.22 mmol) and isopropanol (1.0 mL). The reaction system was heated to reflux for 16h, then cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to thin layer silica gel to prepare a plate (CH) ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a white solid (20 mg, 62.7% yield).

MS(ESI,pos.ion)m/z:469.0[M+H] ⁺ .

¹ H NMR(600MHz,CDCl ₃ )δ(ppm)9.09(d,J＝6.6Hz,1H),8.19(s,1H),7.62(d,J＝4.5Hz,2H),7.49-7.52(m,J＝4.2Hz,1H),5.86-5.77(m,1H),4.69-4.61(m,1H),4.23-4.15(m,1H),3.23-3.04(m,2H),3.03-2.91(m,2H),2.76(s,3H),1.64(d,J＝10.4Hz,3H).

Example 2 (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3-hydroxycyclobutyl) quinazolin-4 (3H) -one

To the reaction flask was added successively (S) -2- (1-aminoethyl) -5-chloro-3- (3-hydroxycyclobutyl) quinazolin-4 (3H) -one (20 mg,0.07 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (30 mg,0.14 mmol), DIPEA (30 mg,0.22 mmol) and isopropanol (1.0 mL). The reaction system was heated to reflux for 16h, then cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to thin layer silica gel to prepare a plate (CH) ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a pink solid (24 mg, 75.2% yield).

MS(ESI,pos.ion)m/z:469.0[M+H] ⁺ .

¹ H NMR(600MHz,CDCl ₃ )δ(ppm)9.45(d,J＝6.0Hz,1H),8.24(s,1H),7.70(d,J＝7.9Hz,1H),7.63(t,J＝7.9Hz,1H),7.49(d,J＝7.6Hz,1H),5.83-5.76(m,1H),5.33-5.22(m,1H),4.96(s,1H),3.62-3.46(m,2H),2.56(s,3H),2.43(dt,J＝22.0,11.9Hz,2H),1.63(d,J＝6.6Hz,3H).

Example 3 2- ((S) -1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (2-hydroxycyclopropyl) quinazolin-4 (3H) -one

First step Synthesis of tert-butyl ((1S) -1- (5-chloro-4-oxo-3- (2- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropyl) -3, 4-dihydroquinazolin-2-yl) ethyl) carbamate

To the reaction flask were added 2-amino-6-chlorobenzoic acid (0.20 g,1.16 mmol), (S) -2- ((t-butoxycarbonyl) amino) propionic acid (0.18 g,1.15 mmol), pyridine (8.0 mL) and triphenyl phosphite (0.85 g,2.74 mmol). The reaction was allowed to react at room temperature for 18H, then 2- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropylamine (0.24 g,1.27 mmol) was added to the system. After the addition was completed, the reaction system was heated to 60℃for 6 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =40/1) afforded the title compound as a colorless liquid (0.17 g, 31% yield).

MS(ESI,pos.ion)m/z:464.4[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.60-7.50(m,2H),7.47-7.41(m,1H),5.79-5.52(m,1H),5.51-5.37(m,1H),4.09-3.81(m,2H),3.74-3.56(m,1H),3.31-3.07(m,1H),1.88-1.78(m,2H),1.70-1.58(m,4H),1.49-1.43(m,12H),1.21-1.11(m,1H),0.94-0.85(m,1H).

Second step Synthesis of 2- ((S) -1-aminoethyl) -5-chloro-3- (2-hydroxycyclopropyl) quinazolin-4 (3H) -one

To the reaction flask was added tert-butyl ((1S) -1- (5-chloro-4-oxo-3- (2- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropyl) -3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (0.34 g,0.73 mmol) and a solution of hydrogen chloride in ethyl acetate (10 mL,3.0 mol/L). The reaction system was reacted at room temperature for 2 hours, and then concentrated under reduced pressure. To the residue was added saturated sodium carbonate solution to the system ph=7, stirred at room temperature for 10min, and extracted with dichloromethane (20 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (0.17 g, yield 83%). MS (ESI, pos.ion) m/z 280.1[ M+H ]] ⁺ .

Step three Synthesis of 2- ((S) -1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (2-hydroxycyclopropyl) quinazolin-4 (3H) -one

To the reaction flask was added 2- ((S) -1-aminoethyl) -5-chloro-3- (2-hydroxycyclopropyl) quinazolin-4 (3H) -one (20 mg,0.07 mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (30 mg,0.14 mmol), DIPEA (30 mg,0.22 mmol) and isopropanol (1.0 mL) in sequence. The reaction system was heated to reflux for 8h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =50/1) afforded the title compound as a white solid (22 mg, 67.6% yield).

MS(ESI,pos.ion)m/z:455.3[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.21(d,J＝23.5,9.4Hz,1H),8.13(s,1H),7.69-7.53(m,2H),7.50-7.41(m,1H),6.28-6.19(m,1H),5.39-5.26(m,1H),3.71(d,J＝14.4Hz,1H),2.68(s,3H),1.80(d,J＝7.0Hz,3H),1.44(d,J＝5.2Hz,1H),1.04-0.96(m,1H).

Example 4 2- ((S) -1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one

Synthesis of tert-butyl ((1S) -1- (5-chloro-4-oxo-3- (2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropyl) -3, 4-dihydroquinazolin-2-yl) ethyl) carbamate

To the reaction flask were added 2-amino-6-chlorobenzoic acid (1.00 g,5.83 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (1.10 g,5.83 mmol), pyridine (20.0 mL) and triphenyl phosphite (3.65 g,11.8 mmol). The reaction system was reacted at room temperature for 18 hours, and then 2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropylamine (1.00 g,5.84 mmol) was added to the system. After the addition was completed, the reaction system was heated to 60℃for 6 hours. After the reaction was completed, it was cooled to room temperature, 3M hydrochloric acid (100 mL) was added thereto, and extracted with ethyl acetate (100 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =50/1) afforded the title compound as a yellow liquid (1.50 g, 54% yield).

MS(ESI,pos.ion)m/z:478.1[M+H] ⁺ .

Second step Synthesis of 2- ((S) -1-aminoethyl) -5-chloro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one

To the reaction flask were added tert-butyl ((1S) -1- (5-chloro-4-oxo-3- (2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropyl) -3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (1.30 g,2.72 mmol) and a dioxane solution of hydrogen chloride (10 mL,3.0 mol/L). The reaction system was reacted at room temperature for 12 hours, and then concentrated under reduced pressure. To the residue was added saturated sodium carbonate solution to the system ph=7, stirred at room temperature for 10min, and extracted with dichloromethane (50 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH(v/v) =10/1) to give the title compound as a green solid (0.32 g, 40% yield).

MS(ESI,pos.ion)m/z:294.2[M+H] ⁺ .

Step three Synthesis of 2- ((S) -1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one

To the reaction flask was added 2- ((S) -1-aminoethyl) -5-chloro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one (60 mg,0.20 mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (60 mg,0.28 mmol), DIPEA (0.2 mL,1.15 mmol) and isopropanol (6.0 mL) in sequence. The reaction system was heated to reflux for 7h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a pale pink solid (90 mg, 94% yield).

MS(ESI,pos.ion)m/z:469.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.63(d,J＝8.2Hz,1H),8.17(s,1H),7.67-7.51(m,2H),7.46(td,J＝6.9,2.1Hz,1H),6.62-6.51(m,1H),4.35-4.28(m,1H),3.29(dd,J＝22.1,12.0Hz,1H),3.10(td,J＝7.5,3.9Hz,1H),1.67(s,3H),1.65(s,3H),1.47-1.37(m,1H),1.34-1.25(m,1H),1.22-1.15(m,1H).

¹³ C NMR(151MHz,CDCl ₃ )δ(ppm)162.6,161.4,160.8,160.5,160.5,158.7,157.9,149.2,134.0,133.7,129.5,126.2,118.2,81.3,64.8,47.1,31.8,25.5,21.3,15.3,11.1.

Example 5 2- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one

To the reaction flask was added 2- ((S) -1-aminoethyl) -5-chloro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one (60 mg,0.20 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (60 mg,0.28 mmol), DIPEA (0.2 mL,1.15 mmol) and isopropanol (6.0 mL). The reaction system was heated to reflux for 7h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a pale pink solid (87 mg, 90.8% yield).

MS(ESI,pos.ion)m/z:469.0[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.02(t,J＝8.5Hz,1H),8.18(s,1H),7.64-7.56(m,2H),7.54-7.42(m,1H),6.63-6.50(m,1H),4.57(s,1H),4.31(dd,J＝11.7,4.4Hz,1H),3.36-3.19(m,1H),3.10(dt,J＝7.6,4.0Hz,1H),1.70(s,3H),1.67(d,J＝6.6Hz,3H),1.40(dd,J＝13.8,6.8Hz,1H),1.32-1.24(m,1H),1.22-1.15(m,1H).

¹³ C NMR(151MHz,CDCl ₃ )δ(ppm)173.1,165.7,161.6,161.4,160.3,159.6,158.7,149.2,134.0,133.6,129.5,126.3,118.2,82.0,64.8,47.2,31.8,25.5,21.1,15.2,11.6.

Example 6 2- ((S) -1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one

To the reaction flask was added 2- ((S) -1-aminoethyl) -5-chloro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one (60 mg,0.20 mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (60 mg,0.28 mmol), DIPEA (0.2 mL,1.15 mmol) and isopropanol (6.0 mL) in sequence. The reaction system was heated to reflux for 7h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a pale pink solid (63 mg, 65.8% yield).

MS(ESI,pos.ion)m/z:469.3[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.02(t,J＝8.0Hz,1H),8.17(s,1H),7.58(d,J＝4.5Hz,2H),7.42(m,2H),6.63-6.50(m,1H),4.50(s,3H),4.20(d,J＝10.8Hz,1H),3.28(t,J＝10.6Hz,1H),2.90-2.84(m,1H),1.68(s,3H),1.63-1.57(m,1H),1.56-1.50(m,1H),1.46-1.38(m,1H).

Example 7 (S) -3- (2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid

First step Synthesis of methyl (S) -3- (2- (1- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate

To the reaction flask were added 2-amino-6-chlorobenzoic acid (2.10 g,12.2 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (2.31 g,12.2 mmol), pyridine (10.0 mL) and triphenyl phosphite (6.1 mL,23.2 mmol). The reaction system was heated to 30℃for reaction overnight, and then methyl 3-aminocyclobutyl formate (1.50 g,11.6 mmol) was added to the system. After the addition was completed, the reaction system was heated to 70℃for 8 hours, and methyl 3-aminocyclobutyl formate (3.00 g,23.2 mmol) was added thereto, followed by reaction at 70℃overnight. After the reaction was completed, it was cooled to room temperature, 3M hydrochloric acid (60 mL) was added thereto, and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound as a white solid (1.4 g, yield 28%).

MS(ESI,pos.ion)m/z:436.1[M+H] ⁺ .

Second step Synthesis of methyl (S) -3- (2- (1-aminoethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate

To the reaction flask was added methyl (S) -3- (2- (1- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate (1.20 g,2.75 mmol), dichloromethane (5.0 mL) and trifluoroacetic acid (2.0 mL). The reaction system was reacted at room temperature for 7 hours. After completion of the reaction, saturated sodium bicarbonate solution (10 mL) was added and extracted with dichloromethane (30 mL. Times.4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by passing through a silica gel column layerAnalysis (CH) ₂ Cl ₂ Purification with MeOH (v/v) =30/1) afforded the title compound as a colorless viscous liquid (0.79 g, 86% yield).

MS(ESI,pos.ion)m/z:336.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.75-7.62(m,1H),7.58-7.43(m,2H),5.35-5.23(m,0.5H),5.04-4.92(m,0.5H),4.19-4.05(m,1H),3.66(d,J＝12.2Hz,3H),3.22-3.07(m,2.5H),3.00(d,J＝8.7Hz,0.5H),2.65-2.52(m,2H),1.35-1.25(m,3H).

Step three Synthesis of methyl (S) -3- (2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate

To the reaction flask were added successively (S) -3- (2- (1-aminoethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (0.12 g,0.36 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (0.10 g,0.46 mmol), DIPEA (0.2 mL,1.15 mmol) and n-butanol (1.5 mL). The reaction was heated to 130 ℃ and allowed to react overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =50/1) afforded the title compound as a white solid (0.12 g, 66% yield).

MS(ESI,pos.ion)m/z:511.3[M+H] ⁺ .

Fourth step Synthesis of (S) -3- (2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid

To the reaction flask was added successively (S) -3- (2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (80.0 mg,0.16 mmol), methanol (1.5 mL), tetrahydrofuran (0.3 mL) and water (0.3 mL). The reaction system was cooled to 0deg.C and lithium hydroxide monohydrate (16.2 mg,0.39 mmol) was added in portions. After the addition was completed, the reaction was transferred to room temperature and allowed to react for 40min. After the reaction is completed, the reaction system is concentrated under reduced pressure. To the residue was added dropwise 2M hydrochloric acid to the system ph=7, and extracted with dichloromethane (10 ml×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate,filtering and concentrating under reduced pressure. Methanol (1.0 mL) was added to the residue, which was stirred at room temperature for 1h, filtered, and dried at 60℃under vacuum for 10h to give the title compound as a white solid (30.5 mg, 39% yield). MS (ESI, pos.ion) m/z 497.1[ M+H ]] ⁺ .

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm)10.25(s,1H),8.62-8.11(m,3H),7.85-7.78(m,1H),7.66-7.56(m,2H),5.82-5.72(m,1H),4.91-4.79(m,1H),3.30-3.13(m,3H),3.01-2.91(m,1H),2.65-2.58(m,1H),2.57(s,3H),2.55-2.52(m,1H),1.58-1.52(m,3H).

Example 8 (S) -3- (2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxamide

To the reaction flask were added methyl (S) -3- (2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate (68 mg,0.13 mmol) and methanolic ammonia (4.0 ml,7.0 mol/L). The reaction system was heated to 40℃for 29h. Cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =30/1) to give the title compound as a pale yellow solid (30.2 mg, yield 46%).

MS(ESI,pos.ion)m/z:496.1[M+H] ⁺ .

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm)9.59-9.40(m,1H),8.20-8.11(m,1H),7.83-7.75(m,1H),7.65-7.52(m,2H),7.44-7.23(m,1H),6.91-6.81(m,1H),5.73-5.64(m,1H),5.11-4.73(m,1H),3.28-3.11(m,2H),3.00-2.74(m,2H),2.65-2.54(m,1H),2.53-2.51(m,3H),1.58-1.47(m,3H).

Example 9 (S) -3- (2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester

To the reaction flask were added successively (S) -3- (2- (1-aminoethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (0.26 g,0.80 mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (0.24 g,1.20 mmol), DIPEA (0.4 mL,2.30 mmol) and n-butanol (1.5 mL). The reaction was heated to 130 ℃ and allowed to react overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =50/1) afforded the title compound as a white solid (0.38 g, 95% yield).

MS(ESI,pos.ion)m/z:511.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.00(d,J＝6.8Hz,0.5H),8.86(d,J＝6.9Hz,0.5H),8.21-8.14(m,1H),7.62-7.53(m,2H),7.48-7.40(m,1H),5.82-5.69(m,1H),5.25-5.15(m,1H),4.83-4.72(m,1H),3.80-3.69(m,3H),3.55-3.43(m,1H),3.31-3.17(m,1H),3.03-2.91(m,1H),2.90-2.77(m,1H),2.75-2.69(m,3H),2.68-2.66(m,1H),1.63-1.57(m,3H).

Example 10 (S) -3- (2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxamide

To the reaction flask were added methyl (S) -3- (2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutylcarboxylate (0.10 g,0.20 mmol) and methanolic ammonia (6.0 mL,7.0 mol/L). The reaction system was heated to reflux for 5 hours, and an ammoniomethanol solution (2.0 mL,7.0 mol/L) was added. The reaction system was continued for 19 hours. After the reaction was completed, heating was stopped, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =30/1) to give the title compound as a white solid (47.3 mg, yield 48%).

MS(ESI,pos.ion)m/z:496.1[M+H] ⁺ .

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm)9.22(d,J＝6.6Hz,0.5H),9.02(d,J＝6.9Hz,0.5H),8.12(s,0.5H),8.09(s,0.5H),7.80-7.71(m,1H),7.60-7.51(m,2H),7.38(s,1H),7.31-7.25(m,1H),7.23-7.10(m,1H),6.89-6.81(m,1H),5.71-5.63(m,1H),5.13-5.05(m,0.5H),4.85-4.76(m,0.5H),3.22-3.05(m,2H),2.99-2.86(m,1H),2.82-2.72(m,1H),2.63(s,1.5H),2.62(s,1.5H),2.57-2.52(m,1H),1.54(d,J＝6.4Hz,1.5H),1.51(d,J＝6.5Hz,1.5H).

Example 11 (S) -3- (2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutyl carboxylic acid

To the reaction flask was added methyl (S) -3- (2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutylformate (0.12 g,0.23 mmol), methanol (1.0 mL) and water (0.2 mL). The reaction was cooled to 0deg.C and lithium hydroxide monohydrate (45 mg,1.06 mmol) was added. After the addition was completed, the reaction system was reacted at 0℃for 6 hours. After the reaction was completed, 2M hydrochloric acid was slowly added dropwise to the system ph=3, and dichloromethane (10 ml×4) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =8/1) to give the title compound as a white solid (43 mg, yield 37%).

MS(ESI,pos.ion)m/z:497.1[M+H] ⁺ .

¹ H NMR(600MHz,DMSO-d ₆ )δ12.25(brs,1H),9.11-9.06(m,1H),8.12-8.08(m,1H),7.79-7.72(m,1H),7.60-7.52(m,2H),7.34(br,2H),5.74-5.65(m,1H),5.17-5.06(m,0.5H),4.93-4.82(m,0.5H),3.24-3.07(m,3H),2.96-2.88(m,0.5H),2.64-2.57(m,4H),2.49-2.45(m,0.5H),1.54(d,J＝6.6Hz,1.5H),1.52(d,J＝6.6Hz,1.5H).

Example 12 (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxamide (isomer 1)

First step Synthesis of methyl (S) -3- (2- (1- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate (isomer 1 and isomer 2)

To the reaction flask was added 2-amino-6-chlorobenzoic acid (2.10 g,12.20 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (2.31 g,12.20 mmol), pyridine (10.0 mL) and triphenyl phosphite (6.10 mL,23.30 mmol) in this order. The reaction system was heated to 30℃for reaction overnight, and then methyl 3-aminocyclobutane formate (1.50 g,11.60 mmol) was added to the above system. The reaction system was heated to 70℃and reacted for 8 hours. Methyl 3-aminocyclobutyl formate (3.00 g,23.20 mmol) was added and the system was allowed to react overnight. After the reaction was completed, the reaction system was cooled to room temperature, 2M hydrochloric acid (60 mL) was slowly added dropwise thereto, and extraction was performed with ethyl acetate (30 ml×3). The combined organic phases were washed successively with saturated citric acid (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound (S) -methyl 3- (2- (1- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutylformate (isomer 1) as a white solid (0.80 g, yield 16%) and the title compound (S) -methyl 3- (2- (1- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutylformate (isomer 2) as a white solid (0.60 g, yield 12%).

Second step Synthesis of methyl (S) -3- (2- (1-aminoethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate (isomer 1)

To the reaction flask was added in order (S) -methyl 3- (2- (1- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutylcarboxylate (isomer 1) (1.70 g,1.95 mmol), dichloromethane (12.0 mL) and trifluoroacetic acid (3.0 mL). The reaction system was reacted at room temperature for 5.5 hours. After the reaction was completed, the system was concentrated under reduced pressure. To the residue was added ethyl acetate (5 mL), the system was adjusted to ph=9 with saturated sodium carbonate solution, and extracted with ethyl acetate (30 ml×3). The organic phases were combined and washed with saturated brine (100 mL)Washing, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =40/1) to give the title compound as a colorless oil (0.46 g, yield 70%). ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.57-7.46(m,2H),7.40(d,J＝7.2Hz,1H),4.70(p,J＝8.6Hz,1H),4.14(q,J＝6.5Hz,1H),3.72(s,3H),3.22(q,J＝9.7Hz,2H),3.00-2.88(m,1H),2.81-2.67(m,2H),1.43(d,J＝6.6Hz,3H).

Step three Synthesis of (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (isomer 1)

To the reaction flask was added successively (S) -3- (2- (1-aminoethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (isomer 1) (0.165 g,0.49 mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (0.12 g,0.59 mmol), DIPEA (0.2 mL,1.15 mmol) and n-butanol (1.0 mL). The reaction system was heated to 130 ℃ for 4h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =80/1) afforded the title compound as a white solid (0.18 g, 72% yield).

MS(ESI,pos.ion)m/z:511.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.35(d,J＝6.9Hz,1H),8.23(d,J＝20.0Hz,1H),7.69-7.52(m,2H),7.51-7.39(m,1H),5.90-5.77(m,1H),5.24(dd,J＝15.2,8.7Hz,1H),4.50(s,3H),3.75(s,3H),3.47(dt,J＝18.8,8.7Hz,3H),2.68(dd,J＝11.9,6.2Hz,1H),2.56(t,J＝10.6Hz,1H),1.62(d,J＝6.6Hz,3H).

Fourth step Synthesis of (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxamide (isomer 1)

To the microwave lock tube were added methyl (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate (isomer 1) (50 mg,0.10 mmol) and ammonia in methanol (2.5 mL,18mmol, 7M). The system was sealed and heated to 40 ℃ for reaction overnight. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =20/1) to give the title compound as a white solid (25 mg, yield 52%).

MS(ESI,pos.ion)m/z:496.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.20(d,J＝6.9Hz,1H),8.10(s,1H),7.74(t,J＝8.0Hz,1H),7.56(dd,J＝19.3,7.8Hz,4H),7.26(s,1H),6.83(s,1H),5.75-5.66(m,1H),4.87-4.76(m,1H),4.54(s,3H),2.98-2.71(m,3H),2.59(dd,J＝21.9,6.9Hz,2H),1.55(d,J＝6.4Hz,3H).

Example 13 (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxamide (isomer 2)

First step Synthesis of methyl (S) -3- (2- (1-aminoethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate (isomer 2)

To the reaction flask was added successively (S) -methyl 3- (2- (1- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate (isomer 2) (0.69 g,1.58 mmol), dichloromethane (6.0 mL) and trifluoroacetic acid (1.5 mL). The reaction system was reacted at room temperature for 5 hours. After the reaction was completed, the system was concentrated under reduced pressure. To the residue was added ethyl acetate (5 mL), the system was adjusted to ph=9 with saturated sodium carbonate solution, and extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =30/1) to give the title compound as a pale yellow solid (0.39 g, yield 74%). ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.55(q,J＝8.1Hz,2H),7.47-7.40(m,1H),5.20-5.10(m,1H),4.22(q,J＝6.6Hz,1H),3.79-3.70(m,3H),3.63-3.41(m,3H),2.62-2.48(m,2H),1.43(d,J＝6.6Hz,3H).

Second step Synthesis of (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (isomer 2)

To the reaction flask was added successively (S) -3- (2- (1-aminoethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (isomer 2) (0.15 g,0.45 mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (0.12 g,0.54 mmol), DIPEA (0.2 mL,1.15 mmol) and n-butanol (0.6 mL). The reaction system was heated to 130 ℃ for 4h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =80/1) afforded the title compound as a white solid (0.20 g, 87% yield).

MS(ESI,pos.ion)m/z:511.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.27(d,J＝6.8Hz,1H),8.10(s,1H),7.74(t,J＝8.0Hz,1H),7.55(dd,J＝19.7,7.9Hz,4H),5.81-5.69(m,1H),4.94(dd,J＝16.6,8.3Hz,1H),4.54(s,3H),3.64(s,3H),3.26-3.00(m,3H),2.60(dd,J＝33.6,7.9Hz,2H),1.54(d,J＝6.4Hz,3H).

Step three Synthesis of (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxamide (isomer 2)

To the microwave lock tube was added methyl (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate (isomer 2) (90 mg,0.18 mmol) and ammonia in methanol (5.0 ml,7 m). Sealing the system, and heating to 70 ℃ to react for 12 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =30/1) to give the title compound as a white solid (40 mg, yield 46%).

MS(ESI,pos.ion)m/z:496.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.40(d,J＝6.5Hz,1H),8.11(s,1H),7.74(t,J＝7.9Hz,1H),7.61(d,J＝8.0Hz,1H),7.52(d,J＝7.6Hz,1H),7.36(s,1H),6.83(s,1H),5.79-5.68(m,1H),5.20-5.08(m,1H),4.55(s,3H),3.24-3.07(m,3H),2.62-2.52(m,2H),2.07-1.94(m,1H),1.53(d,J＝6.4Hz,3H).

¹³ C NMR(151MHz,DMSO-d ₆ )δ(ppm)177.3,162.1,161.1,160.4,159.0,158.2,158.0,148.8,134.5,132.9,129.6,126.6,118.4,82.3,50.3,48.4,32.7,30.2,30.1,21.4.

Example 14 (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid (isomer 1)

To the reaction flask was added in order (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (isomer 1) (94 mg,0.18 mmol), methanol (1.0 mL) and water (0.2 mL). The reaction system was cooled to 0deg.C and lithium hydroxide monohydrate (41 mg,0.98 mmol) was added. After the addition was completed, the reaction system was heated to 40℃for 6 hours. After the reaction was completed, methylene chloride (5 mL) was added thereto, the system was adjusted to ph=2 with a 10% aqueous solution of citric acid, and extracted with ethyl acetate (10 ml×4). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as an off-white solid (32 mg, 35% yield).

MS(ESI,pos.ion)m/z:497.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.29(d,J＝6.1Hz,1H),8.61(s,1H),8.52(brs,2H),7.81(t,J＝7.9Hz,1H),7.66(d,J＝7.9Hz,1H),7.59(d,J＝7.7Hz,1H),5.89-5.76(m,1H),5.11-4.97(m,1H),4.60(s,3H),3.32-3.13(m,4H),2.65-2.56(m,1H),1.55(d,J＝6.3Hz,3H).

Example 15 (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid (isomer 2)

To the reaction flask was added in order (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (isomer 2) (0.12 g,0.23 mmol), methanol (1.5 mL) and water (0.3 mL). The reaction was cooled to 0deg.C and lithium hydroxide monohydrate (47 mg,1.12 mmol) was added. After the addition, the reaction system was heated to 40℃for 50min. After the reaction was complete, the system was adjusted to ph=2 with 1M hydrochloric acid and extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as an off-white solid (39 mg, 35% yield).

MS(ESI,pos.ion)m/z:497.3[M+H] ⁺ .

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm)9.26(d,J＝6.6Hz,1H),8.09(s,1H),7.74(t,J＝7.9Hz,1H),7.55(dd,J＝19.3,7.9Hz,4H),5.79-5.69(m,1H),4.94-4.82(m,1H),4.54(s,3H),3.18-3.08(m,3H),2.98-2.87(m,2H),2.62(s,1H),1.54(d,J＝6.3Hz,3H).

Example 16 (S) -2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

Synthesis of tert-butyl (S) - (1- (5-chloro-3- (3- (hydroxymethyl) cyclobutyl) -4-oxo-3, 4-dihydro-quinazolin-2-yl) ethyl) carbamate

To the reaction flask were added 2-amino-6-chlorobenzoic acid (0.50 g,2.90 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (0.58 g,3.10 mmol), pyridine (1.5 mL) and triphenyl phosphite (1.0 mL,3.50 mmol). The reaction system was heated to 55℃for 18 hours, and then (3-aminocyclobutyl) methanol hydrochloride (0.29 g,2.90 mmol) was added to the system. After the addition was completed, the reaction system was heated to reflux for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 4M hydrochloric acid (3.0 mL) was added, and the mixture was extracted with ethyl acetate (20 mL. Times.4). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound as a white solid (41 mg, yield 4%).

MS(ESI,pos.ion)m/z:408.1[M+H] ⁺ .

Second step Synthesis of (S) -2- (1-aminoethyl) -5-chloro-3- (3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one trifluoroacetate salt

To the reaction flask were added tert-butyl (S) - (1- (5-chloro-3- (3- (hydroxymethyl) cyclobutyl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (30 mg,0.07 mmol), dichloromethane (0.5 mL) and trifluoroacetic acid (0.2 mL). The reaction system was reacted at room temperature for 0.5h, then concentrated under reduced pressure to give the title compound as a white solid (31 mg, yield 100%).

Third step Synthesis of (S) -2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

To the reaction flask was added successively (S) -2- (1-aminoethyl) -5-chloro-3- (3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one trifluoroacetate (31 mg,0.07 mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (25 mg,0.12 mmol), DIPEA (0.2 mL,1.15 mmol) and n-butanol (1.0 mL). The reaction system was heated to 130 ℃ and reacted for 1.5h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a pale yellow solid (12 mg, 34% yield).

MS(ESI,pos.ion)m/z:483.3[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.34-9.21(m,1H),8.16-8.06(m,1H),7.79-7.66(m,1H),7.64-7.42(m,4H),5.82-5.68(m,1H),4.88-4.76(m,1H),4.60-4.44(m,3H),3.53-3.45(m,2H),3.17-2.88(m,2H),2.66-2.55(m,2H),2.27-1.93(m,2H),1.59-1.46(m,3H).

Example 17 (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

Synthesis of tert-butyl ((1S) -1- (5-chloro-3- (3- (hydroxymethyl) cyclobutyl) -4-oxo-1, 2,3, 4-tetrahydroquinazolin-2-yl) ethyl) carbamate

To a solution of methyl (S) -3- (2- (1- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-4-oxoquinazolin-3 (4H) -yl) cyclobutylcarboxylate (0.36 g,0.83 mmol) in ethanol (3.0 mL) was added sodium borohydride (0.15 g,3.95 mmol). The reaction was allowed to react overnight at room temperature, then quenched by the addition of 10% citric acid solution (20 mL) and extracted with ethyl acetate (20 mL. Times.4). The organic phases were combined, washed successively with saturated citric acid solution (20 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (0.34 g, yield 100%).

MS(ESI,pos.ion)m/z:410.2[M+H] ⁺ .

To a solution of tert-butyl ((1S) -1- (5-chloro-3- (3- (hydroxymethyl) cyclobutyl) -4-oxo-1, 2,3, 4-tetrahydroquinazolin-2-yl) ethyl) carbamate (0.34 g,0.83 mmol) in dichloromethane (6.0 mL) was added DDQ (0.40 g,1.76 mmol). The reaction system is reacted for 4 hours at room temperature, and then the reaction system is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =3/1) to give the title compound as a white solid (0.11 g, yield 31%). MS (ESI, pos.ion) m/z 408.2[ M+H ] ] ⁺ .

Third step Synthesis of (S) -2- (1-aminoethyl) -5-chloro-3- (3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

To the reaction flask were added tert-butyl (S) - (1- (5-chloro-3- (3- (hydroxymethyl) cyclobutyl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (0.22 g,0.54 mmol), dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL). The reaction was allowed to react overnight at room temperature. After the reaction was completed, methylene chloride (10 mL) was added thereto, and saturated sodium carbonate was added dropwiseThe solution was brought to system ph=9 and extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as a white solid (98 mg, 59% yield).

MS(ESI,pos.ion)m/z:308.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.72-7.64(m,1H),7.58-7.44(m,2H),5.20-4.81(m,1H),4.71-4.45(m,1H),4.22-4.11(m,1H),3.59-3.44(m,2H),3.04-2.89(m,1H),2.69-2.53(m,1H),2.43-2.30(m,1H),2.26-2.03(m,3H),1.36-1.27(m,3H).

Fourth step Synthesis of (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

To the reaction flask was added successively (S) -2- (1-aminoethyl) -5-chloro-3- (3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one (60 mg,0.20 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (60 mg,0.28 mmol), DIPEA (0.1 mL,0.57 mmol) and n-butanol (0.5 mL). The reaction system was heated to 130 ℃ for 3h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as a white solid (69 mg, yield 74%).

MS(ESI,pos.ion)m/z:483.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.52-9.39(m,1H),8.20-8.08(m,1H),7.86-7.47(m,5H),5.74-5.64(m,1H),5.04-4.73(m,1H),4.72-4.67(m,0.5H),4.53-4.46(m,0.5H),3.55-3.46(m,2H),3.05-2.90(m,1H),2.68-2.55(m,1.5H),2.50(s,3H),2.44-2.31(m,1H),2.29-2.05(m,1.5H),1.60-1.41(m,3H).

Example 18 (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-8-fluoro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid

First step Synthesis of methyl (S) -3- (2- (1- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-8-fluoro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate

To the reaction flask were added 2-amino-6-chloro-3-fluorobenzoic acid (1.13 g,5.96 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (1.13 g,5.96 mmol), pyridine (2.5 mL) and triphenyl phosphite (2.8 mL,10.84 mmol). The reaction system was heated to 30℃for reaction overnight, and then methyl 3-aminocyclobutane-1-carboxylate (0.70 g,5.42 mmol) was added to the system. After the addition was completed, the reaction system was heated to 70℃and reacted overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, 4M hydrochloric acid (5 mL) was added, and the mixture was extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound as a white solid (137 mg, yield 6%).

MS(ESI,pos.ion)m/z:354.1[M-Boc+H] ⁺ .

Second step Synthesis of methyl (S) -3- (2- (1-aminoethyl) -5-chloro-8-fluoro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate

To the reaction flask was added (S) -3- (2- (1- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-8-fluoro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (0.12 g,0.26 mmol), dichloromethane (4.0 mL) and trifluoroacetic acid (1.0 mL). The reaction system was allowed to react for 3h at room temperature. After the reaction was completed, a saturated sodium carbonate solution was added dropwise thereto to the system ph=9, and extracted with ethyl acetate (10 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =30/1) afforded the title compound as a pale green solid (64 mg, 72% yield).

MS(ESI,pos.ion)m/z:354.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.40-7.29(m,2H),5.25-5.12(m,1H),4.24(q,J＝6.6Hz,1H),3.75(s,3H),3.58-3.38(m,3H),2.58(dt,J＝9.4,5.2Hz,2H),1.45(d,J＝6.7Hz,3H).

Step three Synthesis of methyl (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-8-fluoro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylate

To the reaction flask was added successively (S) -3- (2- (1-aminoethyl) -5-chloro-8-fluoro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (65 mg,0.18 mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (50 mg,0.24 mmol), DIPEA (0.1 mL,0.57 mmol) and n-butanol (1.0 mL). The reaction system was heated to 130 ℃ for 4h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =30/1) afforded the title compound as a white solid (90 mg, 93% yield).

MS(ESI,pos.ion)m/z:529.2[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.32(d,J＝7.0Hz,1H),8.22(s,1H),7.44-7.32(m,2H),5.97-5.86(m,1H),5.28-5.17(m,1H),4.52(s,3H),3.77(s,3H),3.59-3.37(m,3H),2.78-2.59(m,2H),1.61(d,J＝6.6Hz,3H).

Fourth step Synthesis of (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-8-fluoro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid

To the reaction flask was added successively (S) -3- (2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-8-fluoro-4-oxoquinazolin-3 (4H) -yl) cyclobutane-1-carboxylic acid methyl ester (90.0 mg,0.17 mmol), methanol (1.0 mL), water (0.2 mL) and lithium hydroxide monohydrate (47 mg,1.12 mmol). The reaction system is heated to 40 ℃ to react for 40min. After the reaction was completed, cooled to room temperature, saturated citric acid was added dropwise thereto to the system ph=5, and extracted with dichloromethane (20 ml×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as an off-white solid (32 mg, 37% yield).

MS(ESI,pos.ion)m/z:515.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.14(d,J＝6.9Hz,1H),8.26(s,1H),8.11(s,1H),7.72-7.62(m,1H),7.60-7.43(m,2H),5.84-5.71(m,1H),5.20-5.05(m,1H),4.51(s,3H),3.27-3.05(m,4H),2.69-2.56(m,1H),1.52(d,J＝6.5Hz,3H).

Example 19- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -8-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one

First step Synthesis of (S) -2- (3- ((tert-Butoxycarbonyl) amino) -2-oxobutyl) -6-chlorobenzoic acid

To the reaction flask were added 2-chloro-6-methylbenzoic acid (1.70 g,10.0 mmol) and anhydrous tetrahydrofuran (30 mL). The reaction was cooled to-30℃and then n-butyllithium solution (10 mL,25.0mmol, 2.5M) was slowly added dropwise. After the dripping is finished, the reaction is kept warm and stirred for 30min, and the system A is marked.

To another reaction flask was added tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (3.0 g,12.9 mmol) and anhydrous tetrahydrofuran (30 mL). The reaction system was cooled to-30℃and then a solution of isopropyl magnesium chloride in tetrahydrofuran (8.0 mL,16.0mmol, 2.0M) was slowly added dropwise. After the dripping is finished, the reaction system is stirred for 30min under heat preservation. The system solution was then slowly added dropwise to system a. After the completion of the dropwise addition, the system was transferred to-15℃for 3 hours. After the reaction was completed, saturated ammonium chloride (50 mL) was added to quench the reaction, followed by extraction with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound as a white solid (3.0 g, yield 88%).

MS(ESI,pos.ion)m/z:364.1[M+Na] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.39-7.28(m,2H),7.16(d,J＝7.0Hz,1H),5.50-5.30(m,1H),3.79(s,2H),1.45(s,9H),1.37(d,J＝6.9Hz,3H).

Synthesis of tert-butyl (S) - (1- (8-chloro-1-oxo-1H-isochroman-3-yl) ethyl) carbamate

To the reaction flask was added (S) -2- (3- ((t-butoxycarbonyl) amino) -2-oxobutyl) -6-chlorobenzoic acid (2.40 g,7.0 mmol) and acetic anhydride (20 mL). The reaction system was heated to 70 ℃ for 9h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =4/1) to give the title compound as a white solid (1.20 g, yield 53%).

MS(ESI,pos.ion)m/z:268.0[M-tBu+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.59-7.47(m,2H),7.31-7.28(m,1H),6.41(s,1H),5.08-4.95(m,1H),4.66-4.54(m,1H),1.49(d,J＝7.0Hz,3H),1.45(s,9H).

Third step (Synthesis of tert-butyl ((2S) -4- (3-chloro-2- ((2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropyl) carbamoyl) phenyl) -3-oxobutan-2-yl) carbamate

To a solution of 2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropylamine (1.20 g,7.0 mmol) in anhydrous dichloromethane (10 mL) at 0deg.C was slowly added dropwise a solution of trimethylaluminum (3.6 mL,7.2mmol, 2.0M). After completion of the dropwise addition, a solution of tert-butyl (S) - (1- (8-chloro-1-oxo-1H-isochroman-3-yl) ethyl) carbamate (0.30 g,0.93 mmol) in anhydrous dichloromethane (10 mL) was continuously added dropwise to the system. After the completion of the dropwise addition, the reaction system was transferred to room temperature for 7 hours, and then the reaction was quenched by addition of saturated sodium chloride solution (20 mL) and extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound as a white solid (0.22 g, yield 48%).

MS(ESI,pos.ion)m/z:517.2[M+Na] ⁺ .

Fourth step Synthesis of 3- ((S) -1-aminoethyl) -8-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one

To the reaction flask was added tert-butyl ((2S) -4- (3-chloro-2- ((2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropyl) carbamoyl) phenyl) -3-oxobutan-2-yl) carbamate (0.22 g,0.44 mmol) and hydrogen chloride in dioxaneRing solution (20 mL, 3.0M). The reaction system was heated to 65 ℃ and reacted for 11h, then cooled to room temperature, and concentrated under reduced pressure. To the residue was added saturated sodium carbonate solution to ph=7, stirred at room temperature for 10min, and extracted with dichloromethane (60 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a white solid (80 mg, 61% yield).

MS(ESI,pos.ion)m/z:293.15[M+H] ⁺ .

Fifth step Synthesis of 3- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -8-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one

To the reaction flask was added 3- ((S) -1-aminoethyl) -8-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one (0.14 g,0.48 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (0.14 g,0.44 mmol), DIPEA (0.3 mL,1.72 mmol) and isopropanol (6.0 mL). The reaction system was heated to reflux for 24h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a grey solid (0.12 g, 54% yield).

MS(ESI,pos.ion)m/z:468.2[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.60(d,J＝6.4Hz,1H),8.03(s,1H),7.56-7.44(m,2H),7.41(d,J＝7.3Hz,1H),6.56(s,1H),5.96-5.84(m,1H),4.70(d,J＝5.0Hz,1H),3.81-3.71(m,1H),3.63-3.48(m,1H),2.91(dd,J＝6.2,3.5Hz,1H),2.46(s,3H),1.60(d,J＝6.7Hz,3H),1.50-1.45(m,1H),1.33-1.25(m,1H).

Example 20- ((S) -1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -8-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one

3- ((S) -1-aminoethyl) -8-chloro-2- (2- (hydroxymethyl) cyclopropyl) was added to the reaction flask) Isoquinolin-1 (2H) -one (30 mg,0.10 mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (27 mg,0.12 mmol), DIPEA (26 mg,0.20 mmol), and n-butanol (4.0 mL). The reaction system was heated to 110 ℃ for 15h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =30/1) afforded the title compound as a white solid (22 mg, 45.4% yield).

MS(ESI,pos.ion)m/z:468.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.71-8.54(m,1H),8.12-8.16(m,1H),7.48-7.37(m,2H),7.29(ddd,J＝17.2,8.5,4.6Hz,1H),6.50-6.54(m,1H),6.35-6.14(m,1H),4.47(d,J＝8.3Hz,3H),4.18(dd,J＝10.9,4.4Hz,1H),3.19(td,J＝10.8,3.7Hz,1H),3.03-2.73(m,1H),1.85-1.53(m,5H),1.28-1.15(m,1H).

Example 21- ((S) -1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -8-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one

To the reaction flask was added 3- ((S) -1-aminoethyl) -8-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one (32 mg,0.11 mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (28 mg,0.13 mmol), DIPEA (28 mg,0.21 mmol) and n-butanol (4.0 mL). The reaction system was heated to 110 ℃ for 15h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =30/1) afforded the title compound as a pale yellow solid (25 mg, yield 55%).

MS(ESI,pos.ion)m/z:468.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.79(d,J＝7.2Hz,1H),8.12(d,J＝13.8Hz,1H),7.47-7.38(m,2H),7.34-7.24(m,1H),6.49(d,J＝16.8Hz,1H),6.27-6.23(m,1H),4.17(dt,J＝12.5,6.2Hz,1H),3.21(t,J＝10.5Hz,1H),3.12-2.94(m,1H),2.68(d,J＝10.7Hz,3H),1.85-1.71(m,1H),1.32(dd,J＝13.6,6.9Hz,1H),1.22-1.15(m,1H),1.04(d,J＝6.6Hz,3H).

Example 22- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-8-fluoro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one

Synthesis of tert-butyl ((1S) -1- (5-chloro-8-fluoro-4-oxo-3- (2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropyl) -3, 4-dihydroquinazolin-2-yl) ethyl) carbamate

To the reaction flask were added 2-amino-6-chloro-3-fluorobenzoic acid (0.50 g,2.64 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (0.50 g,2.64 mmol), pyridine (12.0 mL) and triphenyl phosphite (2.00 g,6.45 mmol). The reaction system was reacted at room temperature for 13 hours, and then 2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropylamine (10.70 g,4.09 mmol) was added to the system. After the addition was completed, the reaction system was heated to 60℃for 6 hours. After the reaction was completed, it was cooled to room temperature, 1M hydrochloric acid (100 mL) was added, and extracted with methylene chloride (100 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =25/1) afforded the title compound as a yellow liquid (1.30 g, 99% yield).

MS(ESI,pos.ion)m/z:496.2[M+H] ⁺ .

Second step Synthesis of 2- ((S) -1-aminoethyl) -5-chloro-8-fluoro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one

To the reaction flask was added tert-butyl ((1S) -1- (5-chloro-8-fluoro-4-oxo-3- (2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropyl) -3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (1.00 g,2.02 mmol), dioxane (25 mL) and concentrated hydrochloric acid (15 mL, 37%). The reaction system was reacted at room temperature for 7 hours, and then concentrated under reduced pressure. To the residue was added saturated sodium carbonate solution to the system ph=7, stirred at room temperature for 10min, and extracted with dichloromethane (100 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CH ₂ Cl ₂ MeOH (v/v) =10/1) to give the title compound as a green solid (30 mg, yield 4.8%).

MS(ESI,pos.ion)m/z:312.15[M+H] ⁺ .

Step three Synthesis of 2- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-8-fluoro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one

To the reaction flask was added 2- ((S) -1-aminoethyl) -5-chloro-8-fluoro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one (30 mg,0.096 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (30 mg,0.14 mmol), DIPEA (0.2 mL,1.15 mmol) and isopropanol (4.0 mL) in sequence. The reaction system was heated to reflux for 6h, then cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to thin layer silica gel to prepare a plate (CH) ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a white solid (35 mg, 75% yield).

MS(ESI,pos.ion)m/z:487.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.35-9.23(m,1H),8.16-8.09(m,1H),7.70-7.63(m,1H),7.54-7.49(m,1H),7.40-7.18(m,2H),6.24-6.14(m,1H),4.81-4.65(m,1H),3.93-3.78(m,1H),3.05-2.94(m,1H),2.47(s,3H),2.05-1.94(m,1H),1.57(d,J＝5.4Hz,3H),1.49-1.41(m,1H),1.04-0.95(m,1H).

Example 23- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2- (2- (hydroxymethyl) cyclopropyl) quinazolin-1 (2H) -one

First step Synthesis of (S) -2- (3- ((tert-Butoxycarbonyl) amino) -2-oxobutyl) -3-chlorobenzoic acid

To the reaction flask were added 3-chloro-2-methylbenzoic acid (5.10 g,30 mmol) and anhydrous tetrahydrofuran (40 mL). The reaction was cooled to-30℃and then n-butyllithium solution (29 mL,72.5mmol, 2.5M) was slowly added dropwise. After the dripping is finished, the reaction is kept warm and stirred for 30min, and the system A is marked.

To another reaction flask was added tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (8.30 g,36 mmol) and anhydrous tetrahydrofuran (40 mL). The reaction was cooled to-30℃and then a solution of isopropyl magnesium chloride in tetrahydrofuran (18.0 mL,36.0mmol, 2.0M) was slowly added dropwise. After the dripping is finished, the reaction system is stirred for 30min under heat preservation. The system solution was then slowly added dropwise to system a. After the completion of the dropwise addition, the system was transferred to-15℃for 3 hours. After the reaction was completed, the reaction was quenched by addition of water (50 mL), followed by addition of ethyl acetate (100 mL) and saturated ammonium chloride solution (100 mL). The mixture was separated, and the aqueous phase was extracted with ethyl acetate (100 mL. Times.2). All organic phases were combined, washed sequentially with saturated ammonium chloride (100 mL), water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =30/1) to give the title compound as a pale yellow liquid (5.6 g, yield 55%).

MS(ESI,pos.ion)m/z:242.1[M-Boc+H] ⁺ .

Synthesis of tert-butyl (S) - (1- (5-chloro-1-oxo-1H-isochroman-3-yl) ethyl) carbamate

To the reaction flask was added (S) -2- (3- ((t-butoxycarbonyl) amino) -2-oxobutyl) -3-chlorobenzoic acid (2.0 g,5.9 mmol) and acetic anhydride (4.1 mL). The reaction system was heated to 65 ℃ and reacted for 6 hours, then cooled to room temperature, and concentrated under reduced pressure. To the residue was added saturated sodium bicarbonate (5 mL) and extracted with ethyl acetate (10 mL. Times.3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =5/1) to give the title compound as a white solid (1.1 g, yield 58%). MS (ESI, pos.ion) m/z 346.1[ M+Na] ⁺ .

Third step Synthesis of tert-butyl ((2S) -4- (2-chloro-6- ((2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropyl) carbamoyl) phenyl) -3-oxobutan-2-yl) carbamate

To a solution of 2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropylamine (2.00 g,12 mmol) in anhydrous dichloromethane (10 mL) at 0deg.C was slowly added dropwise a solution of trimethylaluminum (6.2 mL,12.4mmol, 2.0M). After the completion of the dropwise addition, the system was stirred at a constant temperature for 30 minutes, and a solution of tert-butyl (S) - (1- (5-chloro-1-oxo-1H-isochroman-3-yl) ethyl) carbamate (0.80 g,2 mmol) in anhydrous dichloromethane (5 mL) was continuously added dropwise to the system. After the completion of the dropwise addition, the reaction system was transferred to room temperature for reaction overnight, then cooled to 0 ℃, quenched by dropwise addition of a saturated potassium sodium tartrate solution (3 mL), and extracted with ethyl acetate (15 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =2/1) to give the title compound as a colorless liquid (0.38 g, yield 30%).

Fourth step Synthesis of 3- ((S) -1-aminoethyl) -5-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one

To the reaction flask was added tert-butyl ((2S) -4- (2-chloro-6- ((2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropyl) carbamoyl) phenyl) -3-oxobutan-2-yl) carbamate (0.30 g,0.61 mmol), isopropanol (5.0 mL) and concentrated hydrochloric acid (5.0 mL, 37%). The reaction was heated to 65 ℃ and reacted overnight, then cooled to 0 ℃, saturated sodium carbonate solution (20 mL) was slowly added, and concentrated under reduced pressure to remove most of the organic solvent. Extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =5/1) to give the title compound as a colorless liquid (0.12 g, yield 67.8%).

Fifth step Synthesis of 3- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one

To the reaction flask was added 3- ((S) -1-aminoethyl) -5-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one (30 mg,0.10 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (26 mg,0.12 mmol), DIPEA (26 mg,0.20 mmol) and n-butanol (1.0 mL). The reaction system was heated to 110 ℃ for 15h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =30/1) afforded the title compound as a pale yellow solid (28 mg, yield 58.6%).

MS(ESI,pos.ion)m/z:468.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.68(d,J＝7.4Hz,1H),8.25-8.27(m,1H),8.12-8.16(m,1H),7.64(t,J＝8.3Hz,1H),7.47-7.25(m,1H),6.96(d,J＝17.9Hz,1H),6.46-6.17(m,1H),4.19(dd,J＝11.0,4.3Hz,1H),3.15-3.18(m,1H),3.08-2.82(m,1H),2.45-2.49(m,3H),1.90-1.49(m,4H),1.42-1.13(m,2H).

Example 24- ((S) -1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one

To the reaction flask was added 3- ((S) -1-aminoethyl) -5-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one (30 mg,0.10 mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (26 mg,0.12 mmol), DIPEA (27 mg,0.20 mmol) and n-butanol (1.0 mL). The reaction system was heated to 110 ℃ for 15h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =30/1) afforded the title compound as a pale yellow solid (31 mg, 64.7% yield).

MS(ESI,pos.ion)m/z:468.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.70(dd,J＝20.8,7.3Hz,1H),8.22(d,J＝8.0Hz,1H),8.08-8.12(m,1H),7.61(dd,J＝9.0,8.0Hz,1H),7.31(td,J＝7.9,5.1Hz,1H),6.91-6.96(m,1H),6.41-6.13(m,3H),4.13(dd,J＝12.7,5.7Hz,1H),3.22-3.09(m,1H),3.03-2.76(m,1H),2.62-2.66(m,3H),2.01(d,J＝11.3Hz,1H),1.63-1.72(m,3H),1.35-1.16(m,2H).

Example 25- ((S) -1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one

To the reaction flask was added 3- ((S) -1-aminoethyl) -5-chloro-2- (2- (hydroxymethyl) cyclopropyl) isoquinolin-1 (2H) -one (30 mg,0.10 mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (26 mg,0.12 mmol), DIPEA (27 mg,0.20 mmol), and n-butanol (1.0 mL). The reaction system was heated to 110 ℃ for 15h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =30/1) afforded the title compound as a pale yellow solid (31 mg, 64.7% yield).

MS(ESI,pos.ion)m/z:468.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.70–8.56(m,1H),8.26(d,J＝8.0Hz,1H),8.20–8.10(m,1H),7.69–7.59(m,1H),7.39–7.30(m,1H),7.05–6.96(m,1H),6.43–6.22(m,1H),4.52–4.40(m,3H),4.24–4.15(m,1H),3.24–3.11(m,1H),3.04–2.80(m,1H),1.76–1.64(m,3H),1.62–1.47(m,1H),1.38–1.29(m,1H),1.24–1.17(m,1H).

Example 26 (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3-hydroxy-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

First step Synthesis of 3-methylenecyclobutyl formic acid

To the reaction flask was added 3-methylenecyclobutylcarbonitrile (1.10 g,11.85 mmol), ethanol (5.0 mL), water (5.0 mL) and potassium hydroxide (2.66 g,68.76 mmol) in sequence. The reaction was heated to reflux overnight, then distilled under reduced pressure to remove ethanol. The residual system was cooled to 10 ℃, concentrated hydrochloric acid was added dropwise to the system ph=1, and extracted with ethyl acetate (10 ml×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a colorless liquid (1.28 g, yield 99%).

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)10.74(s,1H),4.88-4.76(m,2H),3.17(ddd,J＝16.2,8.7,7.5Hz,1H),3.08-2.99(m,2H),2.99-2.87(m,2H).

Second step Synthesis of tert-butyl N- (3-methylenecyclobutyl) carbamate

To 3-methylenecyclobutylcarboxylic acid (13.00 g,0.12 mol) and Et ₃ DPPA (57.40 g,0.21 mol) was added dropwise to a solution of N (25.0 mL,0.18 mol) in t-butanol (100.0 mL). After the completion of the dropwise addition, the reaction system was heated to reflux for reaction overnight, and then cooled to room temperature. The reaction was quenched by the addition of water (100 mL) and tert-butanol was removed under reduced pressure. Saturated ammonium chloride (100 mL) was added thereto, and the mixture was filtered. The filter cake was washed with saturated ammonium chloride (60 mL) and saturated sodium bicarbonate (60 mL) and dried under vacuum to give the title compound as a pale yellow solid (14.60 g, 66% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)5.94(s,1H),4.79-4.67(m,2H),4.08-3.93(m,1H),2.88-2.82(m,2H),2.62-2.52(m,2H),1.36(s,9H).

Third step Synthesis of 3-methylene Cyclobutylamine

To the reaction flask was added tert-butyl N- (3-methylenecyclobutyl) carbamate (10.05 g,54.84 mmol), dichloromethane (54.0 mL) and trifluoroacetic acid (14.0 mL) in this order. The reaction was allowed to react overnight at room temperature, then concentrated under reduced pressure. To the residue were added dichloromethane (20 mL) and methanol (4 mL), the system was adjusted to ph=10 with saturated aqueous sodium carbonate, and extracted with dichloromethane (30 ml×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =20/1) to give the title compound as a pale red solid (4.56 g, yield 100%).

Synthesis of tert-butyl (S) - (1- (5-chloro-3- (3-methylenecyclobutyl) -4-oxo-3, 4-dihydro-quinazolin-2-yl) ethyl) carbamate

To the reaction flask was added 2-amino-6-chlorobenzoic acid (2.00 g,11.70 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (2.32 g,12.30 mmol), pyridine (55.0 mL) and triphenyl phosphite (5.43 g,17.50 mmol) in this order. The reaction system was heated to 55℃and reacted for 16h. 3-methylene-cyclobutane (1.06 g,12.80 mmol) was added to the above system. The reaction system was heated to 70℃for reaction for 6 hours, and then concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (60 mL. Times.3). The organic phases were combined, washed successively with 10% aqueous citric acid (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =10/1) to give the title compound as a pale yellow solid (1.13 g, yield 24.9%).

MS(ESI,pos.ion)m/z:390.2[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.64-7.49(m,2H),7.43(dd,J＝6.7,2.1Hz,1H),5.96(d,J＝7.6Hz,1H),5.15-5.01(m,1H),4.95(s,2H),4.88-4.70(m,1H),4.00-3.79(m,2H),3.15-2.91(m,2H),1.46(d,J＝3.6Hz,12H).

Fifth step (S) - (Synthesis of tert-butyl 1- (5-chloro-3- (3-hydroxy-3- (hydroxymethyl) cyclobutyl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate

To the reaction flask were successively added tert-butyl (S) - (1- (5-chloro-3- (3-methylenecyclobutyl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (0.30 g,0.77 mmol), tert-butanol (2.50 mL) and water (2.50 mL). The reaction system was cooled to-10℃and AD-Mix- α (1.18 g) was added thereto. The reaction system was transferred to room temperature and reacted for 20 hours. AD-Mix- α (0.25 g) was added to the reaction system, and the reaction was continued at room temperature overnight. After completion of the reaction, water (20 mL) and sodium sulfite solid (1.00 g) were added to the system, and stirred at room temperature for 1h. Extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =1/2) to give the title compound as a brown solid (0.19 g, yield 56%).

MS(ESI,pos.ion)m/z:424.2[M+H] ⁺ .

Sixth step Synthesis of (S) -2- (1-aminoethyl) -5-chloro-3- (3-hydroxy-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

To the reaction flask was added tert-butyl (S) - (1- (5-chloro-3- (3-hydroxy-3- (hydroxymethyl) cyclobutyl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (0.18 g,0.42 mmol), dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL) in this order. The reaction was reacted at room temperature for 4 hours, and then concentrated under reduced pressure. Dichloromethane (10 mL) was added to the residue, the system was adjusted to ph=10 with saturated sodium carbonate, and extracted with dichloromethane (10 ml×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow solid (0.14 g, yield 100%).

MS(ESI,pos.ion)m/z:324.1[M+H] ⁺ .

Seventh step Synthesis of (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3-hydroxy-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

To the reaction flask was added successively (S) -2- (1-aminoethyl) -5-chloro-3- (3-hydroxy-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one (0.14 g,0.42 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (0.11 g,0.50 mmol), n-butanol (1.0 mL) and DIPEA (0.3 mL,1.72 mmol). The reaction system was heated to 130℃and reacted for 4h. After the reaction was completed, it was cooled to room temperature, and thereto were added dichloromethane (10 mL), methanol (2 mL) and water (20 mL), followed by extraction with dichloromethane (10 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =20/1) to give the title compound as an off-white solid (0.12 g, 60% yield).

MS(ESI,pos.ion)m/z:499.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.60-7.51(m,2H),7.47-7.42(m,1H),5.99-5.86(m,1H),5.23-5.02(m,2H),4.08-3.92(m,2H),3.60-3.39(m,2H),2.69-2.51(m,2H),1.52-1.46(m,12H).

Example 27 (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3-fluoro-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

First step Synthesis of tert-butyl 1-oxaspiro [2.3] hex-5-ylcarbamate

To the reaction flask were added tert-butyl N- (3-methylenecyclobutyl) carbamate (4.00 g,21.80 mmol) and dichloromethane (50.0 mL). The reaction system was cooled to 0deg.C and m-chloroperoxybenzoic acid (6.00 g,26.20mmol, 85%) was added in portions. After the addition was completed, the reaction system was reacted at 0℃for 2 hours. After the reaction was completed, the system was transferred to a separating funnel, washed with 10% sodium sulfite solution (50 mL), saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =3/1) to give the title compound as a white solid (2.40 g, yield 56%).

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)4.79(br.s,1H),4.30-4.01(m,1H),2.80-2.63(m,4H),2.45-2.31(m,2H),1.44(s,9H).

Second step Synthesis of tert-butyl (3-fluoro-3- (hydroxymethyl) cyclobutyl) carbamate

To the reaction flask were added pyridine hydrofluoric acid salt (2.38 g,21.80mmol, content 70%) and dichloromethane (15 mL). The reaction was cooled to-10℃and a solution of tert-butyl 1-oxaspiro [2.3] hex-5-ylcarbamate (2.40 g,12.00 mmol) in methylene chloride (10.0 mL) was slowly added dropwise thereto. After the completion of the dropwise addition, the reaction system was reacted at-10℃for 2 hours, and then transferred to room temperature for further reaction for 4 hours. After completion of the reaction, the system was slowly poured into saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (30 ml×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound as a colorless liquid (1.02 g, yield 39%).

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)4.81(br.s,1H),4.37-4.19(m,1H),3.70(dd,J＝19.7,6.1Hz,2H),2.72-2.56(m,2H),2.04-2.21(m,2H),1.43(s,9H).

Third step (Synthesis of 3-amino-1-fluorocyclobutyl) methoxide hydrochloride

To a mixture of concentrated hydrochloric acid (3.0 mL, 37% in content) and ethyl acetate (6.0 mL) was added tert-butyl (3-fluoro-3- (hydroxymethyl) cyclobutyl) carbamate (1.02 g,4.65 mmol). The reaction was allowed to react at room temperature for 0.5h, then concentrated under reduced pressure. Toluene (10 mL) was added to the residue, and the mixture was concentrated again under reduced pressure to give the title compound as a yellow solid (0.72 g, yield 99.5%)

Synthesis of tert-butyl (S) - (1- (5-chloro-3- (3-fluoro-3- (hydroxymethyl) cyclobutyl) -4-oxo-3, 4-dihydroquinazolin-2-yl) carbamate

To the reaction flask was added 2-amino-6-chlorobenzoic acid (0.60 g,3.49 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (0.70 g,3.67 mmol), pyridine (18.0 mL) and triphenyl phosphite (1.63 g,5.24 mmol) in this order. The reaction system was heated to 55℃and reacted for 24 hours. To the above system was added (3-amino-1-fluorocyclobutyl) methanol hydrochloride (0.72 g,4.63 mmol). The reaction system was heated to 70℃for 16h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. To the residue were added water (30 mL) and ethyl acetate (50 mL), and the mixture was stirred for 10min and separated. The aqueous phase was extracted with ethyl acetate (40 mL. Times.3). All organic phases were combined, washed successively with 10% aqueous citric acid (40 mL. Times.3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound as a pale yellow solid (0.28 g, yield 18%).

MS(ESI,pos.ion)m/z:426.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)13.17(s,1H),8.27(d,J＝6.6Hz,1H),7.98(s,1H),7.88(s,1H),7.57(t,J＝9.0Hz,1H),7.50(dd,J＝8.6,5.0Hz,1H),7.22(s,2H),6.67(s,1H),6.40(s,1H),4.91-4.73(m,1H),2.59(s,3H),1.42(d,J＝6.8Hz,3H).

Fifth step Synthesis of (S) -2- (1-aminoethyl) -5-chloro-3- (3-fluoro-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one hydrochloride

To a solution of tert-butyl (S) - (1- (5-chloro-3- (3-fluoro-3- (hydroxymethyl) cyclobutyl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (0.25 g,0.59 mmol) in ethyl acetate (2.0 mL) was added concentrated hydrochloric acid (1.0 mL, 37%). The reaction was reacted at room temperature for 0.5h, and then concentrated under reduced pressure. Toluene (10 mL) was added to the residue, and the mixture was concentrated again under reduced pressure to give the title compound as a pale yellow solid (0.21 g, yield 98.8%).

MS(ESI,pos.ion)m/z:326.1[M+H] ⁺ .

Sixth step Synthesis of (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3-fluoro-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

To the reaction flask were added successively (S) -2- (1-aminoethyl) -5-chloro-3- (3-fluoro-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one hydrochloride (90 mg,0.25 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (63 mg,0.30 mmol), n-butanol (1.0 mL) and DIPEA (0.1 mL,0.57 mmol). The reaction system was heated to 130℃and reacted for 4h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =30/1) to give the title compound as a white solid (70 mg, yield 56.2%).

MS(ESI,pos.ion)m/z:501.4[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.50-9.26(m,1H),8.22-8.09(m,1H),7.92-7.47(m,5H),5.83-5.61(m,1H),5.24-5.09(m,1H),5.07-4.94(m,1H),3.83-3.60(m,2H),3.28-3.08(m,2H),2.70-2.51(m,5H),1.61-1.45(m,3H).

Example 28 (S) -2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3-fluoro-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

To the reaction flask was added successively (S) -2- (1-aminoethyl) -5-chloro-3- (3-fluoro-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one hydrochloride (70 mg,0.19 mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (49 mg,0.23 mmol), n-butanol (0.5 mL) and DIPEA (0.1 mL,0.57 mmol). The reaction system was heated to 130℃and reacted for 4h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =30/1) to give the title compound as a white solid (41 mg, yield 42%).

MS(ESI,pos.ion)m/z:501.0[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.24-9.12(m,1H),8.17-8.10(m,1H),7.81-7.70(m,1H),7.66-7.58(m,1H),7.58-7.44(m,3H),5.88-5.76(m,1H),5.29-5.15(m,1H),5.09-4.98(m,1H),4.59-4.48(m,3H),3.80-3.60(m,2H),3.28-3.03(m,2H),2.66-2.54(m,1H),2.47-2.32(m,1H),1.62-1.50(m,3H).

¹⁹ F NMR(376MHz,DMSO-d ₆ )δ(ppm)-156.25.

Example 29 (S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (3-fluoro-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one

To the reaction flask were added successively (S) -2- (1-aminoethyl) -5-chloro-3- (3-fluoro-3- (hydroxymethyl) cyclobutyl) quinazolin-4 (3H) -one hydrochloride (30 mg,0.08 mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (25 mg,0.09 mmol), n-butanol (0.5 mL) and DIPEA (35 mg,0.25 mmol). The reaction system was heated to 130℃and reacted for 4h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =30/1) to give the title compound as a white solid (20 mg, yield 48.9%).

MS(ESI,pos.ion)m/z:501.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.02-8.85(m,1H),8.15-8.06(m,1H),7.79-7.69(m,1H),7.62-7.50(m,2H),7.44-7.13(m,2H),5.84-5.61(m,1H),5.26-4.98(m,1H),4.46-4.24(m,1H),3.79-3.58(m,2H),3.27-2.97(m,2H),2.93-2.79(m,1H),2.62-2.56(m,3H),2.46-2.29(m,1H),1.59-1.46(m,3H).

¹⁹ F NMR(376MHz,DMSO-d ₆ )δ(ppm)-156.50.

Example 30 (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -3- (3- (hydroxymethyl) cyclobutyl) -5-methylquinazolin-4 (3H) -one

Synthesis of tert-butyl (S) - (1- (3- (3- (hydroxymethyl) cyclobutyl) -5-methyl-4-oxo-3, 4-dihydro-quinazolin-2-yl) ethyl) carbamate

To the reaction flask were added 2-amino-6-methylbenzoic acid (1.60 g,10.6 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (2.10 g,11.1 mmol), pyridine (53 mL) and triphenyl phosphite (4.93 g,15.9 mmol). The reaction system was heated to 55℃for 16h, and then (3-aminocyclobutyl) methanol hydrochloride (1.60 g,11.6 mmol) was added to the system. After the addition was completed, the reaction system was heated to 70℃for 16h, and was then heated to reflux overnight. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. Water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed successively with 10% aqueous citric acid (50 mL. Times.2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =3/1) to give the title compound as a colorless transparent solid (78 mg, yield 1.9%).

MS(ESI,pos.ion)m/z:388.1[M+H] ⁺ .

Second step Synthesis of (S) -2- (1-aminoethyl) -3- (3- (hydroxymethyl) cyclobutyl) -5-methylquinazolin-4 (3H) -one hydrochloride

To the reaction flask was added tert-butyl (S) - (1- (3- (3- (hydroxymethyl) cyclobutyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (78 mg,0.20 mmol), ethyl acetate (1.0 mL) and concentrated hydrochloric acid (0.5 mL, 37%). The reaction system was reacted at room temperature for 0.5h, then concentrated under reduced pressure to give the title compound as a pale yellow solid (65 mg, yield 100%).

MS(ESI,pos.ion)m/z:288.3[M+H] ⁺ .

Third step (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -3- (3- (hydroxymethyl) cyclobutyl) -5-methylquinazolin-4 (3H) -one

To the reaction flask was added (S) -2- (1-aminoethyl) -3- (3- (hydroxymethyl) cyclobutyl) -5-methyl-quinazolin-4 (3H) -one hydrochloride (60 mg,0.18 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (50 mg,0.24 mmol), n-butanol (1.0 mL) and DIPEA (50 mg,0.39 mmol) in sequence. The reaction system was heated to 130℃and reacted for 4h. After the reaction was completed, it was cooled to room temperature and filtered. The filter cake was purified by silica gel column chromatography (DCM/MeOH (v/v) =3/1) to give the title compound as a white solid (33 mg, 39% yield).

MS(ESI,pos.ion)m/z:463.3[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.60-9.50(m,1H),8.19-8.09(m,1H),7.79-7.54(m,3H),7.52-7.45(m,1H),7.32-7.23(m,1H),5.76-5.62(m,1H),5.02-4.89(m,1H),4.83-4.67(m,1H),4.56-4.45(m,1H),3.57-3.47(m,2H),3.08-2.95(m,1H),2.83-2.72(m,3H),2.71-2.59(m,2H),2.50-2.48(m,3H),2.41-2.16(m,2H),2.16-1.92(m,1H),1.55-1.47(m,3H).

Example 31 (S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2- (3- (hydroxymethyl) cyclobutyl) -8-methylisoquinolin-1 (2H) -one (isomer 1) and

Example 32 (S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2- (3- (hydroxymethyl) cyclobutyl) -8-methylisoquinolin-1 (2H) -one (isomer 2)

First step (Synthesis of 3- ((Boc) amino) cyclobutyl) methanol benzoate

To the reaction flask was added tert-butyl N- (3- (hydroxymethyl) cyclobutyl) carbamate (2.00 g,9.94 mmol), triethylamine (4.5 mL,32.00 mmol) and dichloromethane (30.0 mL) in this order. The reaction system was cooled to-10℃and benzoyl chloride (2.3 mL,20.00 mmol) was added dropwise thereto. After the completion of the dropwise addition, the reaction system was transferred to room temperature for 4 hours, followed by quenching the reaction by adding water (30 mL). Extracted with dichloromethane (30 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =10/1) to give the title compound as a white solid (2.33 g, yield 82%).

MS(ESI,pos.ion)m/z:328.1[M+Na] ⁺ .

Second step (3-aminocyclobutyl) methanolate hydrochloride Synthesis

To the reaction flask was added (3- ((t-butoxycarbonyl) amino) cyclobutyl) methanol benzoate (1.22 g,3.99 mmol), ethyl acetate (5.0 mL) and concentrated hydrochloric acid (2.5 mL, content 37%) in this order. The reaction was reacted at room temperature for 0.5h, and then concentrated under reduced pressure. The residue was concentrated under reduced pressure to remove water by toluene (10 mL. Times.3) to give the title compound as a white solid (0.97 g, yield 100%).

MS(ESI,pos.ion)m/z:206.2[M+H] ⁺ .

Third step (Synthesis of 3- (2, 6-dimethylbenzoylamino) cyclobutyl) methanobenzoate

To the reaction flask was added 2, 6-dimethylbenzoic acid (1.80 g,12.00 mmol), dichloromethane (24.0 mL) and DMF (0.1 mL,1.00 mmol) in this order. Oxalyl chloride (2.0 mL,24.00 mmol) was added dropwise to the reaction system. After the completion of the dropwise addition, the system was reacted overnight at room temperature. After the reaction was completed, the system was concentrated under reduced pressure, and anhydrous methylene chloride (15 mL) was added to the residue to obtain an acid chloride solution.

To another reaction flask was added (3-aminocyclobutyl) methanobenzoate hydrochloride (2.90 g,12.00 mmol), dichloromethane (30.0 mL) and triethylamine (5.0 mL,36.00 mmol). The reaction system was cooled to-5℃and the acid chloride solution prepared above was added dropwise thereto. After the completion of the dropwise addition, the system was reacted overnight at room temperature. After the reaction was completed, the reaction was quenched by adding water (30 mL) to the system, and extracted with methylene chloride (30 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =3/1) to give the title compound as a pale yellow solid (2.50 g, yield 62%).

MS(ESI,pos.ion)m/z:338.2[M+H] ⁺ .

Synthesis of tert-butyl (S) - (4- (2- ((3- (hydroxymethyl) cyclobutyl) carbamoyl) -3-methylphenyl) -3-oxobutan-2-yl) carbamate

To the reaction flask was added (3- (2, 6-dimethylbenzoylamino) cyclobutyl) methanobenzoate (2.50 g,7.41 mmol) and anhydrous tetrahydrofuran (25.0 mL). The reaction was cooled to-30℃and then n-butyllithium (11.5 mL,28.75mmol, 2.5M) was slowly added dropwise. After the dripping is finished, the system is stirred for 2 hours under heat preservation, and is marked as a system A.

To another reaction flask was added tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (2.07 g,8.91 mmol) and anhydrous tetrahydrofuran (20.0 mL). The reaction was cooled to-30℃and then slowly added dropwise magnesium isopropylchloride (6.30 mL,12.60mmol, 2.0M). After the dripping is finished, the system is stirred for 2 hours under heat preservation. The system solution was then slowly added dropwise to system a. After the addition was completed, the system was transferred to-15℃for reaction overnight. After the reaction was completed, the reaction was quenched by adding water (10 mL), and then 10% aqueous citric acid (30 mL) and methanol (10 mL) were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (30 mL. Times.3). All organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a white solid (3.00 g, yield 100%).

MS(ESI,pos.ion)m/z:427.3[M+Na] ⁺ .

Fifth step Synthesis of (S) -3- (1-aminoethyl) -2- (3- (hydroxymethyl) cyclobutyl) -8-methylisoquinolin-1 (2H) -one

To the reaction flask was added tert-butyl (S) - (4- (2- ((3- (hydroxymethyl) cyclobutyl) carbamoyl) -3-methylphenyl) -3-oxobutan-2-yl) carbamate (3.00 g,7.42 mmol), methanol (20.0 mL) and concentrated hydrochloric acid (20.0 mL, content 37%). The reaction was heated to reflux overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, and the system was concentrated under reduced pressure. To the residue was added dichloromethane (20 mL) and methanol (4 mL), the system was adjusted to ph=10 with saturated aqueous sodium carbonate, and extracted with dichloromethane (30 ml×4). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =20/1) to give the title compound as a pale yellow solid (0.82 g, yield 39%).

MS(ESI,pos.ion)m/z:287.3[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.40(t,J＝7.6Hz,1H),7.24(s,1H),7.16(d,J＝7.3Hz,1H),6.54(d,J＝18.2Hz,1H),5.07(p,J＝8.6Hz,1H),4.20(q,J＝6.4Hz,1H),3.78(d,J＝6.5Hz,2H),3.39(dd,J＝20.4,10.0Hz,2H),2.91(s,3H),2.86-2.74(m,1H),2.16-2.06(m,2H),1.43(d,J＝6.5Hz,3H).

Sixth step (S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2- (3- (hydroxymethyl) cyclobutyl) -8-methylisoquinolin-1 (2H) -one (isomer 1)

(S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2- (3- (hydroxymethyl) cyclobutyl) -8-methylisoquinolin-1 (2H) -one (isomer 2)

To the reaction flask was added successively (S) -3- (1-aminoethyl) -2- (3- (hydroxymethyl) cyclobutyl) -8-methylisoquinolin-1 (2H) -one (0.16 g,0.56 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (0.15 g,0.68 mmol), n-butanol (1.5 mL) and DIPEA (148.0 mg,1.15 mmol). The reaction system was heated to 130 ℃ for 4h and then cooled to room temperature. To this was added dichloromethane (20 mL) and water (20 mL), and the mixture was extracted with dichloromethane (20 mL. Times.3). The organic phases were combined, washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =20/1) to give the title compound (S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2- (3- (hydroxymethyl) cyclobutyl) -8-methylisoquinolin-1 (2H) -one (example 31 (isomer 1)) as a pale yellow solid (65 mg, yield 25.2%) and (S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2- (3- (hydroxymethyl) cyclobutyl) -8-methylisoquinolin-1 (2H) -one (isomer 32 (isomer 2)) as a pale yellow solid (90 mg, yield 34.9%).

Example 31 (isomer 1)

MS(ESI,pos.ion)m/z:462.3[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.33(d,J＝7.7Hz,1H),8.21(s,1H),7.43(t,J＝7.6Hz,1H),7.25(s,1H),7.19(d,J＝7.4Hz,1H),6.51(s,1H),5.86-5.78(m,1H),4.89-4.78(m,1H),3.87(s,1H),3.70(d,J＝3.1Hz,2H),3.21(ddd,J＝19.7,19.0,11.6Hz,2H),2.89(s,3H),2.43(s,3H),2.41-2.33(m,2H),2.12-2.02(m,1H),1.64(d,J＝6.6Hz,3H).

Example 32 (isomer 2)

MS(ESI,pos.ion)m/z:462.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.35-8.16(m,2H),7.41(t,J＝7.6Hz,1H),7.24(s,1H),7.18(d,J＝7.2Hz,1H),6.47(s,1H),5.84-5.70(m,1H),4.88(p,J＝8.4Hz,1H),3.69-3.56(m,2H),3.36(ddd,J＝41.4,19.5,9.9Hz,2H),2.90(s,3H),2.68(s,1H),2.42(s,3H),2.11(t,J＝9.9Hz,1H),1.77(t,J＝9.8Hz,1H),1.62(d,J＝6.5Hz,3H).

Example 33- ((S) -1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -2- (2- (hydroxymethyl) cyclopropyl) -8-methylisoquinolin-1 (2H) -one

First step Synthesis of tert-butyl 2, 3-dibromopropionate

To the reaction flask were added tert-butyl acrylate (100 g,0.78 mol) and methylene chloride (300 mL). The reaction was cooled to 0deg.C, and then a solution of bromine (189 g,0.12 mol) in methylene chloride (300 mL) was slowly added dropwise. After the completion of the dropwise addition, the system was reacted at 0℃for 1 hour. After completion of the reaction, it was transferred to a separating funnel, washed with saturated sodium sulfite (500 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (219 g, yield 97%).

Second step Synthesis of tert-butyl 2-nitrocyclopropanecarboxylate

To a solution of nitromethane (44.0 g,0.71 mol) in dimethyl sulfoxide (100 mL) was added potassium carbonate (298 g,2.12 mol). The reaction system was stirred at 25℃for 20min, then a solution of tert-butyl 2, 3-dibromopropionate (183 g,0.64 mol) in dimethyl sulfoxide (300 mL) was slowly added dropwise thereto over a period of about 5 hours. After the completion of the dropwise addition, the system was reacted overnight at room temperature. After the reaction was completed, the system was poured into 1L of ice water, and extracted with methylene chloride (500 mL. Times.3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =20/1) to give the title compound as a yellow oil (78.0 g, yield 60%).

Third step (2-nitrocyclopropyl) methanol Synthesis

To a solution of tert-butyl 2-nitrocyclopropcarboxylate (10.0 g,53.4 mmol) in ethylene glycol dimethyl ether (300 mL) was added sodium borohydride (6.3 g,160.2 mmol) and aluminum trichloride (7.1 g,53.4 mmol). The reaction was allowed to react overnight at room temperature. After the reaction was completed, the system was poured into ice water (800 mL), 2M hydrochloric acid was added dropwise to the system ph=2, and extracted with dichloromethane (300 ml×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow liquid (3.37 g, yield 53.9%).

Synthesis of fourth step (((2-nitrocyclopropyl) methoxy) methyl) benzene

To a solution of (2-nitrocyclopropyl) methanol (0.5 g,4.3 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (0.3 g,7.5mmol, 60%). The reaction system was stirred at room temperature for 5 hours, and then benzyl bromide (0.9 g,5.4 mmol) was added thereto. The reaction was allowed to react overnight at room temperature. After the reaction was complete, the system was poured into saturated ammonium chloride (100 mL) and extracted with dichloromethane (50 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) =1/1) to give the title compound as a yellow oil (0.27 g, yield 31%).

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.39-7.30(m,5H),4.52(s,2H),4.29(dt,J＝6.7,3.2Hz,1H),3.64(dd,J＝10.3,4.7Hz,1H),3.44(dd,J＝10.4,5.8Hz,1H),2.36-2.25(m,1H),1.90-1.82(m,1H),1.35-1.31(m,1H).

Fifth step Synthesis of 2- ((benzyloxy) methyl) cyclopropylamine

To a solution of (((2-nitrocyclopropyl) methoxy) methyl) benzene (1.7 g,8.3 mmol) in isopropanol (75 mL) was added 1M hydrochloric acid (50 mL,50 mmol) and zinc powder (10.9 g,0.17 mol). The reaction system was reacted at room temperature for 2 hours. After the reaction was complete, it was cooled to 0℃and then saturated sodium bicarbonate solution (20 mL) was added. The system was transferred to room temperature and stirred for 0.5h, filtered. The filtered mother liquor was extracted with dichloromethane (10 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) =1/20) to give the title compound as a white solid (0.72 g, yield 49%).

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.40-7.26(m,5H),4.54(s,2H),3.42(dd,J＝10.3,6.3Hz,1H),3.21(dd,J＝10.3,7.8Hz,1H),2.28-2.19(m,1H),1.18-1.06(m,1H),0.66-0.57(m,1H),0.50-0.40(m,1H).

Sixth step Synthesis of (S) -2- (3- ((tert-Butoxycarbonyl) amino) -2-oxobutyl) -6-methylbenzoic acid

To the reaction flask were added 2, 6-dimethylbenzoic acid (5.00 g,33.3 mmol) and anhydrous tetrahydrofuran (70.0 mL). The reaction was cooled to-30℃and then n-butyllithium (40.0 mL,0.10mol, 2.5M) was slowly added dropwise. After the dripping is finished, the system is stirred for 0.5h under heat preservation, and is marked as a system A.

To another reaction flask was added tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (11.62 g,50.0 mmol) and anhydrous tetrahydrofuran (70.0 mL). The reaction was cooled to-30℃and then slowly added dropwise isopropyl magnesium chloride (35.0 mL,70.0mmol, 2.0M). After the dripping is finished, the system is stirred for 0.5h under heat preservation. The system solution was then slowly added dropwise to system a. After the completion of the dropwise addition, the system was transferred to-15℃for 2 hours, and then transferred to room temperature for overnight reaction. After the reaction was completed, the reaction was quenched by adding water (100 mL), and then 4M hydrochloric acid was added to adjust the system to ph=1, followed by extraction with ethyl acetate (200 ml×3). All organic phases were combined, washed with water (200 mL. Times.2) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) =2/1) to give the title compound as a pale yellow viscous liquid (8.60 g, yield 80.3%).

MS(ESI,neg.ion)m/z:320.2[M-H]-.

Seventh step Synthesis of tert-butyl (S) - (1- (8-methyl-1 oxo-1H-isochroman-3-yl) ethyl) carbamate

To the reaction flask was added (S) -2- (3- ((t-butoxycarbonyl) amino) -2-oxobutyl) -6-methylbenzoic acid (2.06 g,6.40 mmol) and acetic anhydride (20 mL). The reaction system was heated to 70 ℃ and reacted overnight. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate (50 mL), which was washed successively with saturated sodium hydrogencarbonate (20 mL. Times.3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) =1/5) to give the title compound as a pale yellow solid (1.64 g, yield 84.5%).

MS(ESI,pos.ion)m/z:248.2[M-(t-Bu)+H] ⁺ .

Eighth step Synthesis of tert-butyl ((2S) -4- (2- ((2- ((benzyloxy) methyl) cyclopropyl) carbamoyl) -3-methylphenyl) -3-oxobutan-2-yl) carbamate

To a solution of 2- ((benzyloxy) methyl) cyclopropylamine (2.2 g,12.4 mmol) in anhydrous dichloromethane (10 mL) was slowly added dropwise trimethylaluminum solution (12.0 mL,24.0mmol, 2.0M) at 0deg.C. After the completion of the dropwise addition, the system was stirred at a constant temperature for 10 minutes, and a solution of tert-butyl (S) - (1- (8-methyl-1-oxo-1H-isochroman-3-yl) ethyl) carbamate (1.5 g,4.9 mmol) in anhydrous dichloromethane (5 mL) was continuously added dropwise to the system. After the completion of the dropwise addition, the reaction system was transferred to room temperature for reaction overnight, and then poured into pre-cooled saturated potassium sodium tartrate (400 mL). The system was adjusted to ph=2 with 2M hydrochloric acid and extracted with dichloromethane (200 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =4/1) to give the title compound as a yellow oil (1.3 g, yield 51%).

MS(ESI,pos.ion)m/z:481.6[M+H] ⁺ .

Synthesis of ninth step 3- ((S) -1-aminoethyl) -2- (2- (hydroxymethyl) cyclopropyl) -8-methylisoquinolin-1 (2H) -one

To the reaction flask was added tert-butyl ((2S) -4- (2- ((2- ((benzyloxy) methyl) cyclopropyl) carbamoyl) -3-methylphenyl) -3-oxobutan-2-yl) carbamate (1.2 g,2.5 mmol), methanol (10 mL) and concentrated hydrochloric acid (10 mL, 37%). The reaction system was heated to reflux for 6h, then cooled to room temperature, and concentrated under reduced pressure. Dichloromethane (50 mL) and saturated sodium bicarbonate (100 mL) were added to the residue, and extracted with dichloromethane (50 ml×3). Combining the organic phases withoutDried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =20/1 gave the title compound as a pale yellow oil (0.54 g, 79% yield).

MS(ESI,pos.ion)m/z:273.3[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.46(t,J＝7.6Hz,1H),7.33-7.29(m,1H),7.21(d,J＝7.3Hz,1H),6.68(s,0.5H),6.50(s,0.5H),4.77-4.61(m,1H),4.24-4.14(m,1H),3.23-3.10(m,1H),2.91-2.86(m,3.5H),2.78-2.70(m,0.5H),1.55(d,J＝6.6Hz,1.5H),1.42(d,J＝6.4Hz,1.5H),1.32-1.24(m,2H),1.24-1.10(m,1H).

Tenth step Synthesis of 3- ((S) -1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -2- (2- (hydroxymethyl) cyclopropyl) -8-methylisoquinolin-1 (2H) -one

To the reaction flask was added 3- ((S) -1-aminoethyl) -2- (2- (hydroxymethyl) cyclopropyl) -8-methylisoquinolin-1 (2H) -one (0.18 g,0.66 mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (0.11 g,0.52 mmol), DIPEA (0.8 mL) and n-butanol (2.5 mL). The reaction was heated to 130 ℃ and allowed to react overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as a white solid (0.17 g, 58% yield).

MS(ESI,pos.ion)m/z:448.3[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.35-8.48(m,1H),8.24-8.10(m,1H),7.50-7.39(m,1H),7.33–7.27(m,1H),7.25-7.17(m,1H),6.42-6.52(m,1H),6.06-6.30(m,1H),4.26–4.14(m,1H),3.79–3.70(m,1H),3.24–3.08(m,1H),2.89(s,3H),2.54-2.42(m,2H),1.70-1.47(m,3H),1.38-1.11(m,3H).

Example 34- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2- (2- (hydroxymethyl) cyclopropyl) -8-methylisoquinolin-1 (2H) -one

To the reaction flask was added 3- ((S) -1-aminoethyl) -2- (2- (hydroxymethyl) cyclopropyl) -8-methylisoquinolin-1 (2H) -one (0.15 g,0.55 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (0.12 g,0.57 mmol), DIPEA (1.0 mL) and n-butanol (2.5 mL). The reaction was heated to 130 ℃ and allowed to react overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as a white solid (0.19 g, 77% yield).

MS(ESI,pos.ion)m/z:448.6[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.73(d,J＝7.0Hz,0.5H),8.66(d,J＝7.4Hz,0.5H),8.18(s,0.5H),8.12(s,0.5H),7.50–7.37(m,1H),7.29–7.25(m,1H),7.25–7.13(m,1H),6.55(s,0.5H),6.47(s,0.5H),6.33–5.89(m,3H),5.37(d,J＝7.3Hz,0.5H),4.83(s,0.5H),4.27–4.16(m,1H),3.74(q,J＝6.9Hz,1H),3.23–3.08(m,1H),2.94–2.84(m,3H),2.80–2.74(m,0.5H),2.75–2.62(m,3H),1.89–1.80(m,0.5H),1.68–1.62(m,3H),1.60–1.48(m,1H).

Example 35- ((S) -1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2- (2- (hydroxymethyl) cyclopropyl) -8-methylisoquinolin-1 (2H) -one

To the reaction flask was added 3- ((S) -1-aminoethyl) -2- (2- (hydroxymethyl) cyclopropyl) -8-methylisoquinolin-1 (2H) -one (0.19 g,0.69 mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (0.15 g,0.69 mmol), DIPEA (1.0 mL) and n-butanol (2.5 mL). The reaction was heated to 130 ℃ and allowed to react overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as a white solid (0.21 g, 67% yield).

MS(ESI,pos.ion)m/z:448.6[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.64–8.46(m,1H),8.25–8.10(m,1H),7.50-7.36(m,1H),7.32-7.28(m,1H),7.24-7.12(m,1H),6.62–6.47(m,1H),6.35-6.11(m,1H),4.54-4.40(m,3H),4.24–4.14(m,1H),3.72(q,J＝7.0Hz,1H),3.18-3.00(m,1H),2.91-2.77(m,4H),1.73-1.68(m,3H),1.30-1.26(m,2H).

Example 36- ((S) -1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -3- (2- (hydroxymethyl) cyclopropyl) -5-methyl quinazolin-4 (3H) -one

Synthesis of tert-butyl ((1S) -1- (3- (2- ((benzyloxy) methyl) cyclopropyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate

To the reaction flask were added 2-amino-6-methylbenzoic acid (1.0 g,6.6 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (1.26 g,6.7 mmol), pyridine (10.0 mL) and triphenyl phosphite (4.3 g,13.2 mmol). The reaction system was heated to 30℃for 16h, and then 2- ((benzyloxy) methyl) cyclopropylamine (1.8 g,10.2 mmol) was added to the system. After the addition, the reaction system was heated to 80℃for 24 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate (50 mL), which was washed successively with 1M hydrochloric acid (50 mL. Times.2), saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =5/1) to give the title compound as a yellow oil (1.9 g, yield 62.0%).

MS(ESI,pos.ion)m/z:464.6[M+H] ⁺ .

Second step Synthesis of 2- ((S) -1-aminoethyl) -3- (2- (hydroxymethyl) cyclopropyl) -5-methylquinazolin-4 (3H) -one

To the reaction flask was added tert-butyl ((1S) -1- (3- (2- ((benzyloxy) methyl) cyclopropyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (1.9 g,4.1 mmol), methanol (12 mL) and concentrated hydrochloric acid (13 mL, 37%). The reaction system was heated to reflux for 10h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. Addition of residue toDichloromethane (50 mL) and saturated sodium bicarbonate solution (25 mL) were extracted with dichloromethane (25 ml×6). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =20/1) afforded the title compound as a colorless liquid (0.95 g, 84% yield).

Step three Synthesis of 2- ((S) -1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -3- (2- (hydroxymethyl) cyclopropyl) -5-methylquinazolin-4 (3H) -one

To the reaction flask was added 2- ((S) -1-aminoethyl) -3- (2- (hydroxymethyl) cyclopropyl) -5-methyl quinazolin-4 (3H) -one (0.27 g,0.99 mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (0.21 g,1.0 mmol), DIPEA (1.0 mL) and n-butanol (2.5 mL). The reaction was heated to 130 ℃ and allowed to react overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as a white solid (0.35 g, 79% yield).

MS(ESI,pos.ion)m/z:449.5[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.21(d,J＝7.2Hz,0.5H),9.07(d,J＝7.7Hz,0.5H),8.19(s,1H),7.67-7.48(m,2H),7.27-7.19(m,1H),6.58-6.48(m,0.5H),6.33-6.24(m,0.5H),4.82-4.72(m,0.5H),4.51(d,J＝6.7Hz,0.5H),4.37-4.15(m,1H),3.81-3.68(m,0.5H),3.28-3.17(m,1H),3.13-3.01(m,0.5H),2.87(s,1.5H),2.84(s,1.5H),2.56(s,1.5H),2.54(s,1.5H),1.67-1.64(m,3H),1.57-1.41(m,2H),1.36-1.30(m,1H).

Example 37- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -3- (2- (hydroxymethyl) cyclopropyl) -5-methylquinazolin-4 (3H) -one

2- ((S) -1-aminoethyl) -3- (2- (hydroxymethyl) cyclopropyl) -5-methylquinazolin-4 (3H) -one (0.25 g,0.92 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidine were added to the reaction flask4-amine (0.19 g,0.9 mmol), DIPEA (1.0 mL), and n-butanol (2.5 mL). The reaction was heated to 130 ℃ and allowed to react overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as a white solid (0.37 g, 89% yield).

MS(ESI,pos.ion)m/z:449.5[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.73-8.47(m,1H),8.18(s,1H),7.64-7.46(m,2H),7.24-7.12(m,1H),6.61-6.28(m,1H),4.95-4.78(m,0.5H),4.60-4.50(m,0.5H),435-4.25(m,0.5H),4.25-4.15(m,0.5H),3.81-3.66(m,0.5H),3.30-3.15(m,1H),3.29-3.03(m,0.5H),2.90-2.82(m,3H),2.78-2.71(m,3H),1.68-1.61(m,3H),1.51-2.34(m,2H),1.24-1.13(m,1H)

Example 38- ((S) -1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -3- (2- (hydroxymethyl) cyclopropyl) -5-methyl quinazolin-4 (3H) -one

To the reaction flask was added 2- ((S) -1-aminoethyl) -3- (2- (hydroxymethyl) cyclopropyl) -5-methyl quinazolin-4 (3H) -one (0.19 g,0.69 mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (0.15 g,0.64 mmol), DIPEA (1.0 mL) and n-butanol (2.5 mL). The reaction was heated to 130 ℃ and allowed to react overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =10/1) afforded the title compound as a white solid (0.22 g, 70% yield).

MS(ESI,pos.ion)m/z:449.5[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.18-8.99(m,1H),8.16(d,J＝4.1Hz,1H),7.64-7.39(m,2H),7.19(t,J＝6.8Hz,1H),6.62-6.34(m,1H),5.19-4.80(m,1H),4.50(s,3H),4.37-4.12(m,1H),3.26-3.09(m,1H),2.90-2.75(m,3H),1.71-1.62(m,6H),1.45-1.35(m,1H),1.27-1.21(m,1H).

Example 39 2- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-6-fluoro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one

Synthesis of tert-butyl ((1S) -1- (3- (2- ((benzyloxy) methyl) cyclopropyl) -5-chloro-6-fluoro-4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate

To the reaction flask were added 6-amino-2-chloro-3-fluorobenzoic acid (1.00 g,5.28 mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (1.05 g,5.55 mmol), pyridine (26.0 mL) and triphenyl phosphite (3.27 g,10.60 mmol). The reaction system was heated to 35℃for 16h, and then 2- ((benzyloxy) methyl) cyclopropylamine (1.12 g,6.33 mmol) was added to the system. After the addition, the reaction system was heated to 80℃for 16h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. To the residue were added ethyl acetate (50 mL) and water (30 mL). The mixture was separated, and the aqueous phase was extracted with ethyl acetate (40 mL. Times.3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =10/1) to give the title compound as a colorless liquid (0.14 g, yield 6%).

MS(ESI,pos.ion)m/z:502.2[M+H] ⁺ .

Second step Synthesis of 2- ((S) -1-aminoethyl) -5-chloro-6-fluoro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one hydrochloride

To the reaction flask was added tert-butyl ((1S) -1- (3- (2- ((benzyloxy) methyl) cyclopropyl) -5-chloro-6-fluoro-4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (0.14 g,0.28 mmol), n-butanol (1.0 mL) and concentrated hydrochloric acid (1.0 mL, 37%). The reaction system was heated to 130 ℃ for reaction for 5h, then cooled to room temperature, and concentrated under reduced pressure. Toluene (10 mL) was added to the residue, and concentrated again under reduced pressure to give the title compound as a yellow solid (97 mg, yield 100%).

MS(ESI,pos.ion)m/z:312.1[M+H] ⁺ .

Step three Synthesis of 2- ((S) -1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-6-fluoro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one

To the reaction flask was added 2- ((S) -1-aminoethyl) -5-chloro-6-fluoro-3- (2- (hydroxymethyl) cyclopropyl) quinazolin-4 (3H) -one hydrochloride (81 mg,0.23 mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (65 mg,0.31 mmol), DIPEA (0.13 g,0.98 mmol) and n-butanol (1.0 mL) in sequence. The reaction system was heated to 130 ℃ for reaction for 6h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ Purification with MeOH (v/v) =30/1) afforded the title compound as a pale yellow solid (69 mg, 58% yield).

MS(ESI,pos.ion)m/z:487.0[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.29-9.19(m,1H),8.10-8.09(m,1H),7.88-7.82(m,1H),7.78-7.40(m,3H),6.11-6.06(m,1H),4.75-4.64(m,1H),3.84-3.80(m,1H),3.66-3.48(m,1H),3.01-2.96(m,1H),2.49(s,3H),1.67-1.40(m,4H),1.33-1.28(m,1H),1.03-0.83(m,1H).

Biological testing

Example a: stability of Compounds in human and rat liver microsomes

Human or rat liver microsomes were incubated in 96-well plates. Typical incubation mixtures included human or rat liver microsomes (20 mg/mL), target compound (1. Mu.M) and NADPH (6.0 mM) potassium phosphate buffer (PBS, 100mM, pH 7.4) in a total volume of 15. Mu.L, compounds were dissolved in DMSO, diluted to 100. Mu.M with 50% ACN, and diluted to 30. Mu.M with PBS. mu.L of 30. Mu.M intermediate solution and 18.8. Mu.L of liver microsomes were added to 456.2. Mu.L of 0.1M potassium phosphate buffer and pre-incubated for 10min.

30. Mu.L of the mixed solution was added to a 96-well plate, 150. Mu.L of the internal standard working solution was immediately added, and 15. Mu.L of the NADPH solution was added thereto, and after mixing, it was placed in a refrigerator at 4℃as an initial 0-point sample. mu.L of the mixed solution was added to 96-well plates at various time points (NCF, 20 and 60 min), 15. Mu.L of NADPH solution was added to wells at time points of 20min and 60min, respectively, and 15. Mu.L of potassium phosphate buffer was added to wells designed as NCF (no cofactor), 60, i.e., without coenzyme, and the reaction was started to start timing. After the end of the time period, 150 μl of pre-chilled internal standard working solution was added to the position at the set time point and incubation ended.

All the above samples were centrifuged at 4000rpm for 5min, and a certain amount of supernatant was taken out and diluted with solvent for LC-MS/MS analysis.

Verapamil served as a positive control, incubated at 37 ℃, and the reactions were terminated at different time points (NCF, 20 and 60 min).

Data analysis

For each reaction, the concentration of compound (expressed as a percentage) in human or rat liver microsome incubation was plotted as a percentage of the relative time points at zero to infer in vivo liver intrinsic clearance CLint (ref.: naritomi Y, tershita S, kimura S, suzuki a, kagayama a, sugiyama y.prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29:1316-1324).

TABLE 1 stability data of examples of the invention in human and rat liver microsomes

The results in table 1 show that the compounds of the present invention have a reasonable half-life in human and rat liver microsomes.

Example B: kinase Activity assay

The activity of the compounds of the invention as PI3K inhibitors can be assessed by the following assay.

General description of kinase assays

Kinase assay by detection of incorporation of gamma- ³³ P-ATP Myelin Basic Protein (MBP). A20. Mu.g/mL buffer solution of MBP (Sigma #M-1891) in tris buffer saline (TBS; 50mM Tris pH 8.0,138mM NaCl,2.7mM KCl) was prepared, coated with a highly binding white 384 well plate (Greiner), 60. Mu.L per well. Incubate at 4℃for 24 hours. After that use100. Mu.L TBS plates were washed 3 times. Kinase reaction in a total volume of 34. Mu.L of kinase buffer (5mM Hepes pH 7.6,15mM NaCl,0.01% bovine serum albumin (Sigma #I-5506), 10mM MgCl ₂ 1mM DTT,0.02%TritonX-100). Compounds were dissolved in DMSO and added to each well with a final concentration of 1% DMSO. Each data was assayed in two passes, with at least two assays for each compound. For example, the final concentration of enzyme is 10nM or 20nM. Addition of unlabeled ATP (10. Mu.M) and gamma-) ³³ P-labeled ATP (2X 10 per well) ⁶ cpm,3000 Ci/mmole). The reaction was run with shaking at room temperature for 1 hour. 384-well plates were washed with 7x PBS and 50 μl of scintillation fluid per well was added. The results were checked with a Wallac Trilux counter. It will be apparent to those skilled in the art that this is just one of many detection methods, as well as others.

IC with suppressed test method ₅₀ And/or inhibition constant K _i 。IC ₅₀ Defined as the concentration of the compound that inhibited 50% of the enzyme activity under the assay conditions. IC was estimated by making a curve containing 10 concentration points using a dilution factor of 1/2log ₅₀ Values (e.g., a typical curve is made with compound concentrations of 10. Mu.M, 3. Mu.M, 1. Mu.M, 0.3. Mu.M, 0.1. Mu.M, 0.03. Mu.M, 0.01. Mu.M, 0.003. Mu.M, 0.001. Mu.M, and 0. Mu.M).

General assay protocol for PI3 kinase

PI3K (p110α/p85α) (h) [ non-radioactive assay ]]

PI3K (p110α/p85α) (h) was incubated in a buffer containing 10. Mu.M phosphatidylinositol-4, 5-bisphosphate and MgATP (at a concentration determined as required). After addition of the ATP solution, the reaction is started. After incubation for 30 minutes at room temperature, a stop solution containing EDTA and biotin phosphatidylinositol-3, 4, 5-triphosphate was added thereto to terminate the reaction. Finally, detection buffer including europium-labeled anti-GST mab, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. The well plate was read in time resolved fluorescence mode and the Homogeneous Time Resolved Fluorescence (HTRF) signal was determined by the equation htrf=10000× (Em 665nm/Em620 nm).

PI3K (p110β/p85α) (h) [ non-radioactive assay]

PI3K (p110β/p85α) (h) was incubated in a buffer containing 10. Mu.M phosphatidylinositol-4, 5-bisphosphate and MgATP (at a concentration determined as required). After addition of the ATP solution, the reaction is started. After incubation for 30 minutes at room temperature, a stop solution containing EDTA and biotin phosphatidylinositol-3, 4, 5-triphosphate was added thereto to terminate the reaction. Finally, detection buffer including europium-labeled anti-GST mab, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. The well plate was read in time resolved fluorescence mode and the Homogeneous Time Resolved Fluorescence (HTRF) signal was determined by the equation htrf=10000× (Em 665nm/Em620 nm).

PI3K (p110δ/p85α) (h) [ non-radioactive assay]

PI3K (p110δ/p85α) (h) was incubated in a buffer containing 10. Mu.M phosphatidylinositol-4, 5-bisphosphate and MgATP (at a concentration determined as required). After addition of the ATP solution, the reaction is started. After incubation for 30 minutes at room temperature, a stop solution containing EDTA and biotin phosphatidylinositol-3, 4, 5-triphosphate was added thereto to terminate the reaction. Finally, detection buffer including europium-labeled anti-GST mab, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. The well plate was read in time resolved fluorescence mode and the Homogeneous Time Resolved Fluorescence (HTRF) signal was determined by the equation htrf=10000× (Em 665nm/Em620 nm).

PI3K (p120γ) (h) [ non-radioactive assay ]]

PI3K (p120γ) (h) was incubated in a buffer containing 10. Mu.M phosphatidylinositol-4, 5-bisphosphate and MgATP (concentration as required). After addition of the ATP solution, the reaction is started. After incubation for 30 minutes at room temperature, a stop solution containing EDTA and biotin phosphatidylinositol-3, 4, 5-triphosphate was added thereto to terminate the reaction. Finally, detection buffer including europium-labeled anti-GST mab, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. The well plate was read in time resolved fluorescence mode and the Homogeneous Time Resolved Fluorescence (HTRF) signal was determined by the equation htrf=10000× (Em 665nm/Em620 nm).

The kinase assay of the present invention was performed by Millipore UK Ltd, dundee Technology Park, dundee DD2 1SW, UK.

Experiments prove that the compound provided by the invention has higher inhibition activity on PI3K beta. Specifically, the inhibition activity of the compound of the invention on PI3K beta is less than 500nm; IC in which most of the compounds are ₅₀ Less than 100nm, preferably part of the compound IC ₅₀ IC of partial compound smaller than 50nm and more preferably ₅₀ Less than 10nm. Among them, the results of inhibition test of some of the compounds of examples are shown in Table 3.

TABLE 3 kinase Activity data for the examples of the invention

In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

1. A compound having one of the following structures:

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound of claim 1; the pharmaceutical compositions optionally further comprise pharmaceutically acceptable adjuvants.

3. Use of a compound of claim 1 or a pharmaceutical composition of claim 2 in the manufacture of a medicament for preventing, treating or alleviating a disease associated with abnormal expression of PI3K beta kinase;

wherein the disease associated with abnormal expression of PI3K beta kinase is acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphoblastic leukemia, chronic myelogenous leukemia, multiple myeloma, T-cell lymphoma, B-cell lymphoma, fahrenheit macroglobulinemia, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, brain cancer or bone cancer.